T-cell lymphoma treatments

ABSTRACT

Described herein are methods for treating T-cell lymphoma in a subject in need thereof, comprising administering to the subject in need thereof, an ETP compound. Also described herein are pharmaceutical compositions and compositions for use that include such ETP compound.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. filed 62/520,921 on Jun. 16, 2017 and U.S. ProvisionalApplication No. 62/520,946 filed on Jun. 16, 2017, which areincorporated herein by reference in their entirety and for all purposes.

BACKGROUND

Malignant cancerous growths, due to their unique characteristics, poseserious challenges for modern medicine. Their characteristics includeuncontrollable cell proliferation resulting in unregulated growth ofmalignant tissue, an ability to invade local and even remote tissues,lack of differentiation, lack of detectable symptoms and, mostsignificantly, lack of effective therapies. There is a need in the artfor treating T-cell lymphomas. Provided here are solutions for these andother needs in the art.

BRIEF SUMMARY

Described herein, inter alia, are methods for treating T-cell lymphomain a subject in need thereof, comprising administering to the subject inneed thereof, an ETP compound. Further provided herein are methods fortreating T-cell lymphoma in a subject in need thereof, comprisingadministering to the subject in need thereof, a bridged ETP compound ora non-bridged ETP compound. Also described herein are pharmaceuticalcompositions and compositions for use that include such ETP compound.

In an aspect, the compound (ETP compound) has the structure of formula(1):

or a pharmaceutically acceptable salt thereof.

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂, —SR^(1D),—SO_(n1)R^(1B), —SO_(n1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(n2)OR^(2B), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), ONR^(2B)R^(2C), NHC(O)NHNR^(2B)R^(2C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C), NHNR^(3B)R^(3C),ONR^(3B)R^(3C), NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂, —SR^(4D),—SO_(n4)R^(4B), —SO_(n4)OR^(4B), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), NHC(O)NHNR^(4B)R^(4C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(5A), —NR^(5B)R^(5C), —COOR^(5A), CONR^(5B)R^(5C), —NO₂, SR^(5D),SO_(n5)R^(5B), SO_(n5)OR^(5B), SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),ONR^(5B)R^(5C), NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, SR^(6D),SO_(n6)R^(6B), SO_(n6)OR^(6B), SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),ONR^(6B)R^(6C), NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(16A), —NR^(6B)R^(16C), —COOR^(16A), —CONR^(6B)R^(16C), —NO₂,—SR^(16D), —SO_(n16)R^(16B), —SO_(n16)OR^(16B), SO_(v16)NR^(16B)R^(16C),—NR^(16B)R^(16C), —ONR^(16B)R^(16C), —NHC(O)NHNR^(16B)R^(16C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(18A), —NR^(18B)R^(18C), —COOR^(18A), —CONR^(18B)R^(18C), —NO₂,—SR^(18D), —SO_(n18)R^(18B), —SO_(n18)OR^(18B),—SO_(v18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C), —ONR^(18B)R^(18C),—NHC(O)NHNR^(18B)R^(18C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶, wherein R²⁸ and R²⁹ are optionally joinedto form *—S_(p)—* wherein p is an integer from 2 to 4 and each *represents the point of attachment to the remainder of the compound.

R²⁵ is hydrogen, —C(O)-L¹-R³², —C(S)-L¹-R³², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R²⁶ is hydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R²⁵ and R²⁶ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene.

R³² and R³³ are independently halogen, substituted or unsubstitutedC₁-C₃ alkyl, substituted or unsubstituted aryl.

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B),R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), and R^(18D) areindependently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

X is independently —F, —Cl, —Br, or —I. n1, n2, n3, n4, n5, n6, n16, andn18 are independently an integer from 1 to 4. v1, v2, v3, v4, v5, v6,v16, and v18 are independently 1 or 2.

In an aspect, the compound has the structure of formula (I):

In an aspect, the compound has the structure of formula (XXI):

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates compound (1).

FIG. 1B shows compound (1) activity against HUT78 CTCL cells.

FIG. 1C shows Romidepsin (FK-228) activity against HUT78 CTCL cells.

FIGS. 2A-2D show compound (1) dose-dependent HUT78 CTCL cellproliferation using carboxy-fluorescein succinimidyl ester (CFSE)staining cell proliferation assay. FIG. 2A shows the cell proliferationassay result at a concentration of 0 nM of compound (1);

FIG. 2B shows the cell proliferation assay result at a concentration of1 nM of compound (1);

FIG. 2C shows the cell proliferation assay result at a concentration of10 nM of compound (1); and FIG. 2D shows the cell proliferation assayresult at a concentration of 100 nM of compound (1).

FIG. 3 illustrates inhibition of HUT78 CTCL cell proliferation bycompound (1) in a dose-and-time-dependent manner.

FIG. 4 illustrates apoptosis of HUT78 CTCL cells by compound (1) in adose-dependent manner.

FIG. 5 illustrates tumor volume comparison in compound (1) regimen(squares) versus FK-228 regimen (triangles) using a HUT78 CTCL mousexenograft model.

FIG. 6 illustrates tumor size comparison in compound (1) regimen versusFK-228 regimen using a HUT78 CTCL mouse xenograft model.

FIG. 7 illustrates tumor weight comparison in compound (1) regimenversus FK-228 regimen using a HUT78 CTCL mouse xenograft model.

FIG. 8A illustrates a structure of compound (2).

FIG. 8B shows compound (2) activity against HUT78 CTCL cellproliferation in dose-dependent manner.

DETAILED DESCRIPTION

T-cell lymphoma represents a subset of non-Hodgkin's lymphoma (NHL). InEurope and North America, T-cell lymphoma accounts for 5-10% of allcases of NHL while in Asia, this percentage is as high as 24%. T-celllymphomas, as a group, carry a poorer prognosis compared to their B cellcounterpart. In the subgroup of patients with a low internationalprognostic index (IPI) score of 1-2, 5-year overall survival (OS) was55% in those with T-cell lymphomas and 71% in those with B-celllymphomas, and this difference in survival was also reflected inpatients with higher IPI scores. T-cell lymphomas, however, represent aheterogeneous group of diseases with variations in clinicalcharacteristics, prognosis, and response to treatment.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS),angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-celllymphoma (ALCL) are the most common subtypes and account for up to 74%of all T-cell lymphomas. AITL tends to occur in elderly patients, andpatients often present with disseminated lymphadenopathy,hepatosplenomegaly, and autoimmune phenomena. ALCL ALK+ typically occursin young men and presentation can be nodal or extranodal, involving theskin, bone, soft tissues, lung, and liver. On the other hand, ALCL ALK−tends to occur in an older population of patients, the presentation isusually nodal, and the disease runs a more aggressive clinical course.PTCL-NOS, represents a heterogeneous category of nodal and extranodal Tcell lymphomas that cannot be grouped into defined entities. Mostpresent with peripheral lymph-node enlargement, B symptoms and, atdiagnosis, the disease is advanced.

Other uncommon T-cell lymphomas include enteropathy-associated T-celllymphoma (EATL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenicT-cell lymphoma (HSTL), and subcutaneous panniculitis-like T-celllymphoma (SPTCL). It is recognized that EATL lymphoma consists of twodistinct forms: classical or type I EATL and type II EATL. Type I EATLis associated with coeliac disease while type II EATL occurs in Asia andis not associated with coeliac disease. ATLL is caused by infection withthe human T-cell-lymphotropic virus type 1 (HTLV-1), and is rare outsideHTLV-I-endemic areas such as the Caribbean, Japan, and parts of centralAfrica. HSTL is rare; patients present with hepatosplenomegaly andsystemic symptoms, and in 20% of cases it occurs in the context ofchronic immune suppression. SPTCL occurs more commonly in women, and isassociated with autoimmune conditions such as systemic lupuserythematosus.

Cutaneous T-cell lymphoma (CTCL) is caused by an expansion of malignantT-cell lymphocytes (involved in cell-mediated immunity) normallyprogrammed to migrate to the skin. These skin-trafficking malignantT-cells migrate to the skin, causing various lesions to appear that maychange shape as the disease progresses, typically beginning as a rashand eventually forming plaques and tumors. The disease generallypresents with skin involvement only, manifested as scaly, erythematouspatches. However, in advanced stages the disease is diffused to thelymph nodes and visceral organs.

CTCL constitutes a rare group of NHLs, occurring in about 4% of theapproximate 500,000 individuals living with the disease. It isestimated, that CTCL affects about 40,000 individuals in the US, withapproximately 2,800 new cases seen annually. CTCL mortality is relatedto the stage of the disease and median survival generally ranging fromabout 12 years in the early stages to only 2.5 years when the diseasehas advanced.

CTCL describes many different disorders with various symptoms andoutcomes. The two most common types are mycosis fungoides (MF) andSezary syndrome.

Mycosis fungoides is the most common type of CTCL, with approximately16,000 to 20,000 cases across the United States, accounting for half ofall CTCLs. The disease looks different in each patient, with skinsymptoms that can appear as patches, plaques, or tumors. Patches areusually flat, possibly scaly, and look like a rash; plaques are thicker,raised, usually itchy lesions that are often mistaken for eczema,psoriasis, or dermatitis; and tumors are raised bumps, which may or maynot ulcerate. It is possible to have more than one type of lesion.

A medical history, physical exam, and skin biopsy may be necessary fordiagnosis. A physician may examine lymph nodes, order various bloodtests, and may conduct other screening tests, such as a chest x-ray or acomputed axial tomography (CAT) scan. Scans are usually not needed forthose with the earliest stages of the disease. Mycosis fungoides isdifficult to diagnose in its early stages because the symptoms and skinbiopsy findings are similar to those of other skin conditions.

Sezary syndrome is an advanced, variant form of mycosis fungoides, whichis characterized by the presence of lymphoma cells in the blood.Extensive thin, red, itchy rashes usually cover over 80 percent of thebody. In certain patients, patches and tumors appear. Patients may alsoexperience changes in the nails, hair, or eyelids, or have enlargedlymph nodes.

Many of the same procedures used to diagnose and stage other types ofcutaneous T-cell lymphomas are used in Sezary syndrome. In addition, aseries of imaging tests may be needed to determine if the cancer hasspread to the lymph nodes or other organs (although that uncommonlyoccurs). These tests may include a CAT scan, a positron emissiontomography (PET) scan, and/or a magnetic resonance imaging (MRI) scan. Abone marrow biopsy may also be done, but is usually not necessary.

Certain Terminology

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group may have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentdisclosure. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. A heteroaryl group substituent may be a —O—bonded to a ring heteroatom nitrogen.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively. A heterocycloalkyl moiety may includeone ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include two optionally different ring heteroatoms (e.g., O, N, S,Si, or P). A heterocycloalkyl moiety may include three optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include four optionally different ring heteroatoms (e.g., O,N, S, Si, or P). A heterocycloalkyl moiety may include five optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include up to 8 optionally different ring heteroatoms (e.g.,O, N, S, Si, or P).

The term “ETP compound or derivative” or “ETP compound” as used herein,means a compound having the structure of formula (1), (I), (I(S)),(I(R)), (II), (II(S)), (II(R)), (II1), (II1(S)), (II1(R)), (II2),(II2(S)), (II2(R)), (II3), (II3(S)), (II3(R)), (II4), (II5), (III),(III(S)), (III(R)), (III1), (III1(S)), (III1(R)), (IV), (IV(S)),(IV(R)), (IV1), (IV1(S)), (IV1(R)), (IV2), (IV2(S)), (V2(R)), (V),(V(S)), (V(R)), (V1), (V1(S)), (V1(R)), (V2), (V2(S)), (V2(R)), (V3),(V3(S)), (V3(R)), (V4), (V4(S)), (V4(R)), (V1), (V1(S)), (V1(R)), (VI1),(VI1(S)), (VII(R))), (XXI), (XXIa), (XXII), (XXII(S)), (XXII(R)),(XXIII), (XXIII(S)), (XXIII(R)), (XXIV), (XXIV(S)), (XXIV(R)), (XXV),(XXV(S)), (XXV(R)), (XXVI), (XXVI(S)), (XXVI(R)), (XXVII), (XXVII(S)),(XXVII (R)), (XXVIII), (XXVIII(S)), (XXVIII(R)), (XXIX), (XXIX (S)),(XXIX (R)), (XXX), (XXXI), (XXI′), (XXII′), (XXIII′), (XXIII′(S)),(XXIII′(R)), (XXIV′), (XXIV′(S)), (XXIV′(R)), (XXV′), (XXV′(S)),(XXV′(R)), (XXVI′), (XXVI′(S)), or (XXVI′(R)), including embodimentsthereof described herein. The term “ETP” is derived from the termepidithiodiketopiperazine. However, ETP compounds provided herein arenot strictly limited to epidithiodiketopiperazine scaffolds as isreadily seen from the formulae provided herein. Therefore, the “ETP”term provided herein is merely a term of convenience to refer to thecompounds disclosed herein and is not intended to limit the scope of theformulae disclosed herein.

The term “bridged” ETP compound or derivative as used herein, means acompound having a sulfide bridge having p sulfurs, i.e. “Sp” in a corestructure, (e.g. S₂ is —S—S—, S₃ is —S—S—S—, S₄ is —S—S—S—S—). Incontrast, the term “non-bridged” ETP compound or derivative as usedherein, means a compound not having sulfide bridge (“Sp”) anywhere inits formula.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, B, As,or Si) may be placed at any interior position of the heteroalkyl groupor at the position at which the alkyl group is attached to the remainderof the molecule. Heteroalkyl is an uncyclized chain. Examples include,but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CHO—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include three optionally different heteroatoms (e.g., O, N, S, Si,or P). A heteroalkyl moiety may include four optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefive optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include up to 8 optionally different heteroatoms(e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

A “fused ring aryl-heterocycloalkyl” is an aryl fused to aheterocycloalkyl. A “fused ring heteroaryl-heterocycloalkyl” is aheteroaryl fused to a heterocycloalkyl. A “fused ringheterocycloalkyl-cycloalkyl” is a heterocycloalkyl fused to acycloalkyl. A “fused ring heterocycloalkyl-heterocycloalkyl” is aheterocycloalkyl fused to another heterocycloalkyl. Fused ringaryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fusedring heterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substituentsdescribed herein. Fused ring aryl-heterocycloalkyl, fused ringheteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, orfused ring heterocycloalkyl-heterocycloalkyl may each independently benamed according to the size of each of the fused rings. Thus, forexample, 6,5 aryl-heterocycloalkyl fused ring describes a 6 memberedaryl moiety fused to a 5 membered heterocycloalkyl. Spirocyclic ringsare two or more rings wherein adjacent rings are attached through asingle atom. The individual rings within spirocyclic rings may beidentical or different. Individual rings in spirocyclic rings may besubstituted or unsubstituted and may have different substituents fromother individual rings within a set of spirocyclic rings. Possiblesubstituents for individual rings within spirocyclic rings are thepossible substituents for the same ring when not part of spirocyclicrings (e.g. substituents for cycloalkyl or heterocycloalkyl rings).Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “thio,” as used herein, means a sulfur that is single bonded tocarbon or to another sulfur.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O) NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″,—NR—C(NR′R″)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′,—ONR′R″, —NR′C═(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C═(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2 m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R″′,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the disclosure includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R″′,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,—NR′C═(O)NR″NR″′R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C═(O)R″, —NR′C(O)—OR″, —NR′OR″,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R″′, and R″′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound of the disclosure includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R″′, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R″′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron(B), Arsenic (As), and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CHF₂, —CHCl₂, —CHBr₂,—CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SCH₃, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl, —OCH₂Br,—OCH₂I, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:

-   -   (i) oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CHF₂, —CHCl₂,        —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SCH₃, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,        —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl, —OCH₂Br, —OCH₂I, unsubstituted        alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (a) oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CHF₂, —CHCl₂,            —CHBr₂, —CH₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SCH₃, —SO₃H, —SO₄H, —SO₂NH₂,            —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,            —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl, OCH₂Br, —OCH₂I,            unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            or heteroaryl, substituted with at least one substituent            selected from: oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,            —CHF₂, —CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂,            —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SCH₃, —SO₃H,            —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,            —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,            —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,            —OCH₂Br, —OCH₂I, unsubstituted alkyl, unsubstituted            heteroalkyl, unsubstituted cycloalkyl, unsubstituted            heterocycloalkyl, unsubstituted aryl, and unsubstituted            heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl.

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, and/orsubstituted or unsubstituted heteroarylene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, and/or unsubstitutedheteroarylene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroarylene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,wherein if the substituted moiety is substituted with a plurality ofsubstituent groups, each substituent group may optionally be different.In embodiments, if the substituted moiety is substituted with aplurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one size-limited substituentgroup, wherein if the substituted moiety is substituted with a pluralityof size-limited substituent groups, each size-limited substituent groupmay optionally be different. In embodiments, if the substituted moietyis substituted with a plurality of size-limited substituent groups, eachsize-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl isa substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 3 to 8 memberedheterocycloalkylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, and/or each substitutedor unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to7 membered heterocycloalkyl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 3 to 7 memberedheterocycloalkylene.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present disclosure. The presentdisclosure is meant to include compounds in racemic and optically pureforms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

Certain compounds of this disclosure may exist in tautomeric forms, allsuch tautomeric forms of the compounds being within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C— or ¹⁴C-enriched carbonare within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

“S_(p)”, “S_(t)”, or “S_(n)” refers to a sulfide bridge having p, t, orn sulfurs (e.g. S₂ is —S—S—, S₃ is —S—S—S—, S₄ is —S—S—S—S—).

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

Description of compounds of the present disclosure is limited byprinciples of chemical bonding.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present disclosure contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present disclosure may exist as salts, suchas with pharmaceutically acceptable acids. The present disclosureincludes such salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereininclude those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present disclosure. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, and quaternary ammonium (methyl iodide, ethyl iodide, and thelike) salts.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of a disease, pathology or condition,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the injury, pathology orcondition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; improving a patient's physical or mental well-being. Thetreatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation.

A “therapeutically effective amount” or “effective amount” is an amountsufficient for a compound to accomplish a stated purpose relative to theabsence of the compound (e.g. achieve the effect for which it isadministered, treat a disease, reduce enzyme activity, increase enzymeactivity, reduce a signaling pathway, or reduce one or more symptoms ofa disease or condition). An example of an “effective amount” is anamount sufficient to contribute to the treatment or reduction of asymptom or symptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

“Patient,” “subject,” “patient in need thereof,” and “subject in needthereof” are herein used interchangeabley and refer to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein. In particular, “disease” or “condition” referto T-cell lymphoma.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present disclosure without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the disclosure.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

By “co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies, for examplealemtuzumab, bendamustine, bexarotene, bleomycin, bortezomib,brentuximab vedotin, carboplatin, carfilzomib, carmustine, cisplatin,cyclophosphamide, cytarabine, dacarbazine, dazatinib, denileukindiftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate, prednisone,prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof. The compound of thedisclosure can be administered alone or can be co-administered to thepatient. Co-administration is meant to include simultaneous orsequential administration of the compound individually or in combination(more than one compound or agent). Thus, the preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease means thatthe disease is caused by (in whole or in part), a symptom of the diseaseis caused by (in whole or in part) the substance or substance activityor function, or a side-effect of the compound (e.g. toxicity) is causedby (in whole or in part) the substance or substance activity orfunction.

The term “T-cell lymphoma” as used herein, means a disease that affectsT-lymphocytes (T-cells). T-cell lymphoma occurs when cells of the immunesystem called T-lymphocytes, a type of white blood cell, grow andmultiply uncontrollably. Cancerous T-cell lymphocytes travel to manyparts of the body, including the lymph nodes, spleen, bone marrow,blood, or other organs, and form a mass called a tumor.

The term “cancer” as used herein, refers to T-cell lymphoma.

Cancer model organism, as used herein, is an organism exhibiting aphenotype indicative of cancer, or the activity of cancer causingelements, within the organism. The term cancer is defined above. A widevariety of organisms may serve as cancer model organisms, and includefor example, cancer cells and mammalian organisms such as rodents (e.g.mouse or rat) and primates (such as humans). Cancer cell lines areunderstood as cells exhibiting phenotypes or genotypes similar to invivo cancers. Cancer cell lines, as used herein, include cell lines fromanimals (e.g. mice) and from humans, such as HUT78.

An “anticancer agent” as used herein refers to a molecule (e.g.compound, peptide, protein, nucleic acid, antibody) used to treat cancerthrough destruction or inhibition of cancer cells or tissues. Anticanceragents may be selective for certain cancers or certain tissues. In someembodiments, anticancer agents herein may include alemtuzumab,bendamustine, bexarotene, bleomycin, bortezomib, brentuximab vedotin,carboplatin, carfilzomib, carmustine, cisplatin, cyclophosphamide,cytarabine, dacarbazine, dazatinib, denileukin diftitox, dexamethasone,doxorubicin, etoposide, everolimus, fludarabine, forodesine,gemcitabine, hydroxydaunorubicin, ifosfamide, imiquimod, interferons,lenalidomide, liposomal doxorubicin, mechlorethamine, methotrexate,methylprednisolone, nelfinavir, oral corticosteroids, panobinostat,pentostatin, pralatrexate, prednisone, prednisolone, psoralen,retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus,topical corticosteroids, vinblastine, vincristine, vinorelbine,vorinostat, or a combination thereof.

The terms “synergy”, “synergism,” “synergistic,” and “synergistictherapeutic effect” are used herein interchangeably and refer to ameasured effect of compounds administered in combination where themeasured effect is greater than the sum of the individual effects ofeach of the compounds administered alone as a single agent.

Compounds

Described herein are compounds (ETP compounds) for use in the methodsprovided herein having the structure of formula (1):

or a pharmaceutically acceptable salt thereof.

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂, —SR^(1D),—SO_(n1)R^(1B), —SO_(n1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(n2)OR^(2B), —SO_(v2)NR^(2B)R^(2C), NHNR^(2B)R^(2C),ONR^(2B)R^(2C), NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂, —SR^(4D),—SO_(n4)R^(4B), —SO_(n4)OR^(4B), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(5A), —NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C), —NO₂, —SR^(5D),—SO_(n5)R^(5B), —SO_(n5)OR^(5B), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), NHC(O)NHNR^(5B)R^(5C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, —SR^(6D),—SO_(n6)R^(6B), —SO_(n6)OR^(6B), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), ONR^(6B)R^(6C), NHC(O)NHNR^(6B)R^(6C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(16B)R^(6C), —COOR^(16A), —CONR^(16B)R^(16C), —NO₂,SR^(16D), SO_(n16)R^(16B), —SO_(n16)OR^(16B), —SO_(v16)NR^(16B)R^(16C),—N—R^(16B)R^(16C), —ONR^(16B)R^(16C), —NHC(O)NHNR^(16B)R^(16C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(18A), —NR^(18B)R^(18C), —COOR^(18A), —CONR^(18B)R^(18C), —NO₂,—SR^(18D), —SO_(n18)R^(18B), —SO_(n18)OR^(18B),—SO_(v18)NR^(18B)R^(18C), —NR^(18B)R^(18C), ONR^(18B)R^(18C),—NHC(O)NHNR^(18B)R^(18C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R²⁸ and R²⁹ are joined to form —S_(p)— wherein p is an integer from 2 to4, or R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶. R²⁵ is hydrogen, —C(O)-L¹-R³²,—C(S)-L¹-R³², substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R²⁶ is hydrogen, —C(O)-L²-R³³,—C(S)-L²-R³³ substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R²⁵ and R²⁶ may optionally bejoined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene.

L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene.

R³² and R³³ are independently hydrogen, halogen, substituted orunsubstituted C₁-C₃ alkyl, substituted or unsubstituted aryl.

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B),R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), and R^(18D) areindependently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

X is independently —F, —Cl, —Br, or —I. n1, n2, n3, n4, n5, n6, n16, andn18 are independently an integer from 1 to 4. v1, v2, v3, v4, v5, v6,v16, and v18 are independently 1 or 2.

In embodiments, R²⁸ and R²⁹ are joined to form —S_(p)— and the compoundhas the formula:

In embodiments, R²⁸ and R²⁹ are joined to form —S₂— and the compound hasthe

In embodiments, R²⁸ and R²⁹ are joined to form —S₃— and the compound hasthe formula:

In embodiments, R²⁸ and R²⁹ are joined to form —S₄— and the compound hasthe formula:

In embodiments, R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶ and the compound has theformula

In embodiments, R²⁵ is hydrogen. In embodiments, R²⁵ is —C(O)-L¹-R³². Inembodiments, R²⁵ is —C(S)-L¹-R³². In embodiments, R²⁵ is substituted orunsubstituted alkyl. In embodiments, R²⁵ is substituted or unsubstitutedheteroalkyl. In embodiments, R²⁵ is substituted or unsubstituted aryl.In embodiments, R²⁵ is substituted or unsubstituted heteroaryl. Inembodiments, R²⁶ is hydrogen. In embodiments, R²⁶ is —C(O)-L²-R³³. Inembodiments, R²⁶ is —C(S)-L²-R³³. In embodiments, R²⁶ is substituted orunsubstituted alkyl. In embodiments, R²⁶ is substituted or unsubstitutedheteroalkyl. In embodiments, R²⁶ is substituted or unsubstituted aryl.In embodiments, R²⁶ is substituted or unsubstituted heteroaryl. Inembodiments, R²⁵ and R²⁶ are joined to form.

Bridged Forms of Compounds

Described herein are compounds (ETP compounds) for use in the methodsprovided herein having the structure of formula (I):

or a pharmaceutically acceptable salt thereof. R¹, R², R³, R⁴, R⁵, R⁶,R¹⁶ and R¹⁸, and p are as described above.

In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

In some embodiments of a compound of formula (I), R¹⁸ is substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In some embodiments of acompound of formula (I), R¹⁶ is hydrogen. In some embodiments of acompound of formula (I), R³ and R⁴ are independently hydrogen. In someembodiments of a compound of formula (I), R¹ is —CN, —COOR^(1A),—CONR^(1B)R^(1C), or substituted or unsubstituted heteroalkyl. In someembodiments of a compound of formula (I), R¹ is —CN. In some embodimentsof a compound of formula (I), R² is —CF₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments of a compound of formula (I), R²is substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl. In some embodiments of a compound of formula (I), R² ismethyl or methoxy. In some embodiments of a compound of formula (I), R⁵and R⁶ are independently hydrogen, halogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted cycloalkyl. In some embodimentsof a compound of formula (I), R⁵ and R⁶ are independently hydrogen,methyl, ethyl, allyl, or cyclopropyl. In some embodiments of a compoundof formula (I), R⁵ and R⁶ are independently hydrogen or unsubstitutedmethyl. In some embodiments of a compound of formula (I), p is 2.

In some embodiments, the compound of formula (I) has the structure offormula (I(S)):

In some embodiments, the compound of formula (I) has the structure offormula (I(R)):

R¹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). Rr may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R¹ may be —CN, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl. R¹ may be —CN or substitutedor unsubstituted alkyl. R¹ may be —CN or unsubstituted alkyl. R¹ may be—CN, or unsubstituted heteroalkyl. R¹ may be hydrogen.

R¹ may be hydrogen, R^(1E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(1E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(1E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), R^(1E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(1E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(1E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹ may be R^(1E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(1E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(1E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(1E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(1E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(1E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R^(1E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹ is R^(1E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R¹ is R^(1E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹ is R^(1E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹ is R^(1E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹ isR^(1E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R¹ is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R¹ is R^(1E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹ is R^(1E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹ is R^(1E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹ is R^(1E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹ is R^(1E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹ is R^(1E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R¹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R¹ may be R^(1E)-substituted or unsubstituted methyl, R^(1E)-substitutedor unsubstituted ethyl, or R^(1E)-substituted or unsubstituted propyl.R¹ may be unsubstituted methyl, unsubstituted ethyl, or unsubstitutedpropyl.

R¹ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, NO₂,or —COOR^(1A). R^(1A) may be hydrogen, C₁-C₃ unsubstituted alkyl, 2 to 5membered unsubstituted heteroalkyl, or 5 or 6 membered unsubstitutedaryl. In embodiments, R¹ is —COOR^(1A), wherein R^(1A) is C₁-C₃unsubstituted alkyl. RIA may be unsubstituted methyl, unsubstitutedethyl, or unsubstituted propyl. R¹ may be —COOCH₃. R¹ may be halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —NH₂, or NO₂. R¹ may be —CN. R¹ may beunsubstituted 2 to 5 membered heteroalkyl.

R^(1E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(1F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(1F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(1F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(1F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(1F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(1F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(1F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹ may be an electron withdrawing group (EWG) (e.g. halogen, —N₃, —NO₂,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CONH₂, or substituted orunsubstituted 2 to 8 membered heteroalkyl). An “electron withdrawinggroup” is used herein according to its common meaning in the art andrefers to a chemical moiety that tends to remove electrons (electrondensity) from a portion of the compound to which it is attached (e.g. adeactivating group). R¹ may be —CN. R¹ may be —NO₂. R¹ may be —CF₃,—CCl₃, —CBr₃, or —CI₃. R¹ may be substituted or unsubstituted 2 to 8membered heteroalkyl. R¹ may be —COOCH₃.

R² may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R⁷ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R² may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R² may be —CN, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl. R² may be —CN or substitutedor unsubstituted alkyl. R² may be —CN or unsubstituted methyl. R² may be—CN, or unsubstituted heteroalkyl. R² may be substituted alkyl orsubstituted heteroalkyl. R² may be hydrogen.

R² may be hydrogen, R^(2E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(2E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(2E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(2E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(2E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(2E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R² may be R^(2E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(2E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(2E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(2E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(2E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(2E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R² is R^(2E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R² is R^(2E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R² is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R² is R^(2E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R² is R^(2E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R² is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R² is R^(2E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R² isR^(2E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R² is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R² is R^(2E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R² is R^(2E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R² is R^(2E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R² is R^(2E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R² is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R² is R^(2E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R² is R^(2E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R² is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(2E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(2F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(2F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(2F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(2F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(2F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(2F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R^(2E) may be unsubstituted pyridine. R^(2E)may be unsubstituted morpholino. R^(2E) may be unsubstituted methyl.

R^(2F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R² may be —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂,—NHNH₂, —ONH₂, R^(2E)-substituted or unsubstituted C₁-C₃ alkyl, or 2 to3 membered R^(2E)-substituted or unsubstituted heteroalkyl. Inembodiments R² is unsubstituted C₁-C₅ alkyl or unsubstituted 2 to 5membered heteroalkyl. In embodiments R² is unsubstituted methyl. Inembodiments R² is unsubstituted methoxy (e.g. —OCH₃).

R² may be R^(2E)-substituted or unsubstituted C₁-C₅ alkyl (e.g.R^(2E)-substituted or unsubstituted methyl). R² may beR^(2E)-substituted C₁-C₅ alkyl. When R² is substituted or unsubstitutedC₁-C₅ alkyl, R^(2E) may be unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl. R^(2E) may be substituted orunsubstituted morpholino (e.g. R^(2F)-substituted or unsubstitutedmorpholino). R² may be R^(2E)-substituted or unsubstituted 2 to 5membered heteroalkyl. When R² is substituted or unsubstituted 2 to 5membered heteroalkyl, R^(2E) may be unsubstituted C₁-C₅ alkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl. R² may be —OCH₃. R² may be unsubstituted methyl. R² may be—CN.

In embodiments, R¹ is halogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃, —CN,—CHO, —CONH₂, or substituted or unsubstituted 2 to 8 memberedheteroalkyl and R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(2E)-substituted orunsubstituted C₁-C₈ alkyl, R^(2E)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(2E)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(2E)-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, R^(2E)-substituted or unsubstituted phenyl orR^(2E)-substituted or unsubstituted 5 or 6 membered heteroaryl. Inembodiments, at least one of R¹ and R² is an electron withdrawing group(EWG) (e.g. halogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃, —CN, —CHO,—CONH₂, or substituted or unsubstituted 3 to 8 membered heteroalkyl.When R¹ is CN, R² may be —CN. When R¹ is halogen, R² may be halogen.When R¹ is —CN, R² may be unsubstituted C₁-C₅ alkyl. When R¹ is —CN, R²may be unsubstituted methyl. When R¹ is unsubstituted 2 to 8 memberedheteroalkyl (e.g. —COOCH₃), R² may be may be unsubstituted C₁-C₅ alkyl.When R¹ is —CN, R² may be R^(2E)-substituted or unsubstituted C₁-C₅alkyl. When R¹ is —CN, R² may be R^(2E)-substituted or unsubstituted 2to 5 membered heteroalkyl. R^(2E) may be unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R² is a polar substituent and provides polarity to thecompounds provided herein (e.g. where R² is a substituted orunsubstituted 2 to 8 membered heteroalkyl). A “polar substituent” isunderstood by one skilled in the art to be a moiety that creates adipole moment, thereby forming a positive or negative charge on amolecule. R² may be an aqueous solubility enhancing substituent (e.g. amoiety that increases the water solubility of the compound), wheregerminal substitution at R² with a substituent other than methylimproves the solubility of the compound in an aqueous medium. Solubilityenhancing substituents may include basic substituents or groups that addpolarity.

R³ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R³ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R³ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R³ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R³ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R³may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R³ may behalogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R³ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R³ may be hydrogen.

R³ may be hydrogen, R^(3E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(3E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(3E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(3E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(3E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(3E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R³ may be R^(3E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(3E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(3E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(3E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(3E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(3E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R³ is R^(3E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R³ is R^(3E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R³ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R³ is R^(3E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R³ is R^(3E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R³ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R³ is R^(3E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R³ isR^(3E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R³ is an unsubstituted cycloalkyl (e.g., C₃-C₅, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R³ is R^(3E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R³ is R^(3E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R³ is R^(3E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R³ is R^(3E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R³ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R³ is R^(3E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R³ is R^(3E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R³ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(3E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(3F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(3F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(3F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(3F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(3F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(3F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(3F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R³ may be hydrogen, halogen, or R^(3E)-substituted or unsubstitutedC₁-C₈ alkyl. R³ may be hydrogen. R³ may be unsubstituted methyl,unsubstituted ethyl, or unsubstituted propyl.

R⁴ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R⁴ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R⁴ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R⁴ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁴ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁴may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁴ may behalogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R⁴ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R⁴ may be hydrogen.

R⁴ may be hydrogen, R^(4E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(4E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(4E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(4E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(4E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(4E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R⁴ may be R^(4E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(4E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(4E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(4E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(4E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(4E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁴ is R^(4E)-substitutedalkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁴ is anunsubstituted alkyl (e.g., C₁-C₅, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁴ is R^(4E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁴ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R⁴ isR^(4E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R⁴ is an unsubstituted cycloalkyl (e.g., C₃-C₅, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁴ is R^(4E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁴ is R^(4E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁴ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R⁴ is R^(4E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R⁴ is R^(4E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R⁴ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(4E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —OCH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(4F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(4F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(4F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), R^(4F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(4F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(4F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(4F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R⁴ may be hydrogen, halogen, or R^(4E)-substituted or unsubstitutedC₁-C₈ alkyl. R⁴ may be hydrogen. R⁴ may be unsubstituted methyl,unsubstituted ethyl, or unsubstituted propyl. In embodiments, R³ and R⁴are hydrogen.

R⁵ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered heteroaryl). R⁵ may be halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁵may be halogen, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁵ may behalogen, or substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, orC₁-C₄ alkyl). R⁵ may be halogen, or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl). R⁵ may be halogen, or substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R⁵ may be halogen, unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl.R⁵ may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R⁵ may be hydrogen.

R⁵ may be hydrogen, R^(5E)-substituted or unsubstituted alkyl(e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(5E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(5E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(5E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(5E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(5E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R⁵ may be R^(5E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(5E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(5E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(1E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(5E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(5E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁵ is R^(5E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁵ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁵ is R^(5E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁵ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R⁵ isR^(5E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R⁵ is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁵ is R^(5E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁵ is R^(5E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁵ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R⁵ is R^(5E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R⁵ is R^(5E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R⁵ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(5E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(5F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(5F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(5F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(5F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(5F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(5F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(5F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R⁵ may be R^(5E)-substituted or unsubstituted C₁-C₈ alkyl,R^(5E)-substituted or unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, or unsubstituted 3 to 5membered heterocycloalkyl. R⁵ may be unsubstituted C₁-C₈ alkyl. R⁵ maybe unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.R⁵ may be methyl, ethyl, or propyl. R⁵ may be unsubstituted methyl. R⁵may be unsubstituted ethyl. R⁵ may be unsubstituted propyl. R⁵ may beunsubstituted allyl. R⁵ may be R^(5E)-substituted alkyl. R^(5E) may beunsubstituted 5 or 6 membered heterocycloalkyl. R^(5E) may beunsubstituted morpholino. In embodiments, R⁵ is substituted orunsubstituted 2 to 8 membered heteroalkyl. R⁵ may be —(CH₂)₃N(CH₃)₃. R⁵may be unsubstituted 3 to 5 membered cycloalkyl. In embodiments, R⁵ isunsubstituted cyclopropyl.

R⁶ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R⁶ may be hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). R⁶ may be halogen, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). R⁶ may be halogen, or substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁶ may be halogen, orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁶ may behalogen, or substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁶ may behalogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R⁶ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R⁶ may be hydrogen.

R⁶ may be hydrogen, R^(6E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(6E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(6E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(6E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(6E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(6E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R⁶ may be R^(6E)-substituted or unsubstitutedalkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(6E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(6E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(6E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(6E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(6E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁶ is R^(6E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁶ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁶ is R^(6E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁶ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R⁶ isR^(6E)-substituted cycloalkyl (e.g., C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R⁶ is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁶ is R^(6E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁶ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁶ is R^(6E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁶ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R⁶ is R^(6E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R⁶ is R^(6E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R⁶ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(6E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(6F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(6F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(6F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(6F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(6F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(6F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(6F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —N—NH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R⁶ may be hydrogen, halogen, R^(6E)-substituted or unsubstituted C₁-C₈alkyl, or unsubstituted phenyl. R⁶ may be hydrogen. R⁶ may be halogen.R⁶ may be R^(6E)-substituted or unsubstituted C₁-C₈ alkyl. R⁶ may beR^(6E)-substituted or unsubstituted C₁-C₅ alkyl. R⁶ may be unsubstitutedC₁-C₈ alkyl. R⁶ may be unsubstituted methyl. R⁶ may be unsubstitutedethyl. R⁶ may be unsubstituted propyl. R⁶ may be unsubstituted allyl. R⁶may be unsubstituted aryl. R⁶ may be unsubstituted phenyl.

R⁵ and R⁶ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, unsubstituted alkyl, orunsubstituted cycloalkyl. R⁵ and R⁶ are independently hydrogen, C₁-C₃unsubstituted alkyl or 3 to 5 membered cycloalkyl. R⁵ and R⁶ areindependently hydrogen, unsubstituted methyl, unsubstituted ethyl,unsubstituted allyl, or unsubstituted cyclopropyl. R⁵ and R⁶ mayindependently be hydrogen or halogen. R⁵ and R⁶ may independently besubstituted or unsubstituted C₁-C₃ alkyl. R⁵ and R⁶ may be unsubstitutedmethyl. R⁵ and R⁶ may independently be unsubstituted methyl orunsubstituted ethyl.

R¹⁶ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹⁶ may be substituted or unsubstituted alkyl. R¹⁶ may besubstituted or unsubstituted C₁-C₈ alkyl. R¹⁶ may be substituted orunsubstituted C₁-C₅ alkyl. R¹⁶ may be substituted or unsubstituted C₁-C₃alkyl. R¹⁶ may be R^(16E)-substituted or unsubstituted alkyl. R¹⁶ may beR^(16E)-substituted or unsubstituted C₁-C₈ alkyl. R¹⁶ may beR^(16E)-substituted or unsubstituted C₁-C₅ alkyl. R¹⁶ may beR^(16E)-substituted or unsubstituted C₁-C₃ alkyl. R¹⁶ may be hydrogen.

R¹⁶ may be hydrogen, R^(16E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(16E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(16E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(16E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(16E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(16E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁶ may be R^(16E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(16E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(16E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(16E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(16E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(16E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁶ isR^(16E)-substituted alkyl (e.g., C₁-C₅, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁶ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁶ is R^(16E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁶ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁶ isR^(16E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁶ is an unsubstituted cycloalkyl (e.g.,C₃—C, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁶ is R^(16E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁶ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁶ is R^(16E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁶ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁶ is R^(16E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁶ is R^(16E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁶ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(16E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(16F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(16F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(16F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(16F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(16F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(16F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(16F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹⁶ may be hydrogen, halogen or substituted or unsubstituted alkyl. R¹⁶may be hydrogen. R¹⁶ may be halogen. R¹⁶ may be substituted orunsubstituted alkyl. R¹⁶ may be substituted or unsubstituted C₁-C₅alkyl. R¹⁶ may be R^(16E)-substituted or unsubstituted alkyl. R¹⁶ may beR^(16E)-substituted or unsubstituted C₁-C₅ alkyl. In embodiments, R³,R⁴, and R¹⁶ are hydrogen.

R¹⁸ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹⁸ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or2 to 4 membered heteroalkyl). R¹⁸ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R¹⁸ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R¹⁸ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R¹⁸ may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹⁸ maybe halogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R¹⁸ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R¹⁸ may be hydrogen.

R¹⁸ may be hydrogen, R^(18E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(18E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(18E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(18E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(18E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(18E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁸ may be R^(18E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(18E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(18E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(18E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(18E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(18E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted alkyl(e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁸ isR^(18E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁸ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁸ is R^(18E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁸ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁸ isR^(18E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁸ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁸ is R^(18E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁸ is R^(18E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁸ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁸ is R^(18E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁸ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(18E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(18F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(18F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(18F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(18F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(18F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(18F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(18F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹⁸ may be substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁸ maybe R^(18E)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(18E)-substituted or unsubstituted phenyl, R^(18E)-substituted orunsubstituted 6 membered heteroaryl, R^(18E)-substituted orunsubstituted 6,6 fused ring aryl-heterocycloalkyl, R^(18E)-substitutedor unsubstituted 6,5 fused ring aryl-heterocycloalkyl,R^(18E)-substituted or unsubstituted 5,6 fused ringaryl-heterocycloalkyl, where R^(18E) and R^(18F) are as describedherein, including embodiments thereof.

R¹⁸ may be R^(18E)-substituted or unsubstituted 5 memberedheterocycloalkyl, R^(18E)-substituted phenyl, R^(18E)-substituted orunsubstituted 6 membered heteroaryl, R^(18E)-substituted orunsubstituted 6,6 fused ring aryl, R^(18E)-substituted or unsubstituted6,6 fused ring heteroaryl, R^(18E)-substituted or unsubstituted 6,5fused ring aryl, R^(18E)-substituted or unsubstituted 6,5 fused ringheteroaryl, R^(18E)-substituted or unsubstituted 5,6 fused ring aryl,R^(18E)-substituted 5,6 fused ring heteroaryl, R^(18E)-substituted orunsubstituted 6,6 fused ring aryl-heterocycloalkyl, R^(18E)-substitutedor unsubstituted 6,5 fused ring aryl-heterocycloalkyl, orR^(18E)-substituted or unsubstituted 5,6 fused ringaryl-heterocycloalkyl.

R¹⁸ may be R^(1E)-substituted or unsubstituted 5 to 6 memberedheteroaryl. The R^(18E)-substituted or unsubstituted 5 to 6 memberedheteroaryl may be R^(18E)-substituted or unsubstituted thiophenyl,R^(18E)-substituted or unsubstituted thiazolyl, R^(18E)-substituted orunsubstituted oxazolyl, R^(18E)-substituted or unsubstituted imidazolyl,or derivatives thereof. R¹⁸ may be R^(18E)-substituted or unsubstitutedphenyl. R¹⁸ may be R^(18E)-substituted or unsubstituted 6 memberedheteroaryl. R¹⁸ may be R^(18E)-substituted or unsubstituted 6,6 fusedring aryl-heterocycloalkyl. The R^(18E)-substituted or unsubstituted 6,6fused ring aryl-heteroaryl may be R^(18E)-substituted or unsubstituteddihydrobenzo[1,4]dioxinyl. R¹⁸ may be R^(18E)-substituted orunsubstituted 6,5 fused ring aryl-heterocycloalkyl orR^(18E)-substituted or unsubstituted 5,6 fused ringaryl-heterocycloalkyl. The R^(18E)-substituted or unsubstituted 6,5 or5,6 fused ring aryl-heterocycloalkyl may be dihydro-indenyl,benzo[1,3]dioxolyl, or indolyl. R^(18E) may be halogen, SO₂Ph,R¹⁸-substituted or unsubstituted C₁-C₅ alkyl, or R^(18F)-substituted orunsubstituted 2 to 5 membered heteroalkyl.

In one embodiment, R¹ and R¹⁸ are not joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R¹and R¹⁶ are not joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R² and R¹⁸ are not joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R²and R¹⁶ are not joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R¹ and R¹⁸ are not hydrogen. In one embodiment thecompound of formula (I) does not have the formula(3R,8S,8aR)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound of formula (I) does not have the formula(3R,8S,8aR)-2-methyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazin-8-ylacetate. In one embodiment the compound of formula (I) does not have theformula(3R,6R,8S,8aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound does not have the formula2,3-dimethyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound does not have the formula3-(hydroxymethyl)-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.

The compound of formula (I) may have the formula:

p, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as described herein.

In the formula (II), X³ is —N═ or —CR⁷═. X⁴ is —N═ or —CR⁸═. X⁵ is —N═or —CR⁹—.

R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C), —NHPNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂, —SR^(8D),—SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), CONR^(10B)R^(10C), —NO₂,—SR^(10D), SO_(n10)R^(10B), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(1B)R^(10C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C), —NO₂,—SR^(11D), —SO_(n11)R^(11B), —SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A),R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A),R^(11B), R^(11C), and R^(11D) are independently hydrogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The symbol n7, n8, n9, n10, n11, and n12 are independently an integerfrom 1 to 4. The symbol v7, v8, v9, v10, v11, and v12 are independently1 or 2.

R⁷ and R⁸ may be joined together to form substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R⁷ and R⁸ may be joinedtogether to form substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R⁷ and R⁸ may be joined together toform substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁷and R⁸ may be joined together to form substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl). R⁷ and R⁸ may be joinedtogether to form R^(7E)-substituted or unsubstituted cycloalkyl (e.g. 3to 8 membered cycloalkyl). R⁷ and R⁸ may be joined together to formR^(7E)-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl). R⁷ and R⁸ may be joined together to formR^(7E)-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁷and R⁸ may be joined together to form R^(7E)-substituted orunsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R⁸ and R⁹ may be joined together to form substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R⁸ and R⁹ may be joinedtogether to form substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R⁸ and R⁹ may be joined together toform substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁸and R⁹ may be joined together to form substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl). R⁸ and R⁹ may be joinedtogether to form R^(8E)-substituted or unsubstituted cycloalkyl (e.g. 3to 8 membered cycloalkyl). R⁸ and R⁹ may be joined together to formR^(8E)-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl). R⁸ and R⁹ may be joined together to formR^(8E)-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁸and R⁹ may be joined together to form R^(8E)-substituted orunsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R¹⁰ and R¹¹ may be joined together to form substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R¹⁰ and R¹¹ may be joinedtogether to form substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R¹⁰ and R¹¹ may be joined together toform substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R¹⁰and R¹¹ may be joined together to form substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl). R¹⁰ and R¹¹ may be joinedtogether to form R^(10E)-substituted or unsubstituted cycloalkyl (e.g. 3to 8 membered cycloalkyl). R¹⁰ and R¹¹ may be joined together to formR^(10E)-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl). R¹⁰ and R¹¹ may be joined together to formR^(10E)-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl).R¹⁰ and R¹¹ may be joined together to form R^(10E)-substituted orunsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

When X³ is —N═, X⁴ may be —CR⁸═ and X⁵ may be —CR⁹═. When X⁴ is —N═, X³may be —CR⁷═ and X⁵ may be —CR⁹═. When X⁵ is —N═, X³ may be —CR⁷═ and X⁴may be —CR⁸═. X³, X⁴, and X⁵ may be —CR⁷═, —CR⁸═, and —CR⁹═respectively.

In embodiments, R⁷ is hydrogen, halogen, —OCH₃, —SO₂, —SO₂—R^(7B),—OR^(7A), —NR^(7B)R^(7C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is hydrogen. Inembodiments, R⁷ is —Br. In embodiments, R⁷ is —Cl. In embodiments, R⁷ is—SO₂—R^(7B) wherein R^(7B) is substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ is —SO₂—R^(7B)wherein R^(7B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁷ is —SO₂—R^(7B) wherein R^(7B) is phenyl. Inembodiments, R⁷ is phenyl. In embodiments, R⁷ is —OR^(7A), whereinR^(7A) is substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is —OR^(7A), wherein R^(7A)is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is —OR^(7A), wherein R^(7A) is substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁷ is —OR^(7A), whereinR^(7A) is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R⁷is —OR^(7A), wherein R^(7A) is substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R⁷ is —NR^(7B)R^(7C), wherein R^(7B) and R^(7C) areunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁷ is —NR^(7B)R^(7C), wherein R^(7B) and R^(7C) aresubstituted or unsubstituted C₁-C₈ alkyl. In embodiments, R⁷ is—NR^(7B)R^(7C), wherein R^(7B) and R^(7C) are substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is —NR^(7B)R^(7C), whereinR^(7B) and R^(7C) are substituted or unsubstituted C₁-C₂ alkyl.

R⁷ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). R⁷ may be halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). R⁷ may be halogen,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R⁷ may be halogen, or substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R⁷ may be halogen, orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R⁷may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R⁷ may be halogen, unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl. R⁷ may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R⁷ may behydrogen.

R⁷ may be hydrogen, R^(7E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(7E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(7E)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₅ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(7E)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(7E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(7E)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). R⁷ may be R^(7E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R^(7E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R^(7E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(1E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(7E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(7E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ isR^(7E)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁷ is R^(7E)-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁷ is R^(7E)-substituted cycloalkyl (e.g., C₃-C₅cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁷is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁷ is R^(7E)-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁷ isR^(7E)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R⁷ is R^(7E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁷ is R^(7E)-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(7E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂, R^(7F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(7F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(7F)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₁-C₆ cycloalkyl), R^(7F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(7F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl or phenyl), or R^(7F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(7F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —N—NH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(8B),—OR^(8A), —NR^(8B)SR^(8C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is hydrogen. Inembodiments, R⁸ is Br. In embodiments, R⁸ is Cl. In embodiments, R⁸ isSO₂—R^(8B) wherein R^(8B) is substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁸ is SO₂—R^(8B)wherein R^(8B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁸ is SO₂—R^(8B) wherein R^(8B) is phenyl. Inembodiments, R⁸ is phenyl. In embodiments, R⁸ is —OR^(8A), whereinR^(8A) is substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ is —OR^(8A), wherein R^(8A)is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁸ is —OR^(8A), wherein R^(8A) is substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁸ is —OR^(8A), whereinR^(8A) is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R⁸is —OR^(8A), wherein R^(8A) is substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R⁸ is —NR^(8B)R^(8C), wherein R^(8B) and R^(8C) areunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁸ is —NR^(8B)R^(8C), wherein R^(8B) and R^(8C) aresubstituted or unsubstituted C₁-C₈ alkyl. In embodiments, R⁸ is—NR^(8B)R^(8C), wherein R^(8B) and R^(8C) are substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁸ is —NR^(8B)R^(8C), whereinR^(8B) and R^(8C) are substituted or unsubstituted C₁-C₂ alkyl.

R⁸ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —Cl₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R⁸ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R⁸ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R⁸ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁸ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R⁸may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁸ may behalogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R⁸ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R⁸ may be hydrogen.

R⁸ may be hydrogen, R^(8E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(8E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(8E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(8E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(8E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(8E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R⁸ may be R^(8E)-substituted or unsubstitutedalkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(8E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(8E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(8E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(8E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(8E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁸ is R^(8E)-substitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁸ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁸ is R^(8E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁸ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R⁸ isR^(8E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R⁸ is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁸ is R^(8E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁸ is R^(8E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁸ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R⁸ is R^(8E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R⁸ is R^(8E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R⁸ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(8E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(8F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(8F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(8F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(8F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(8F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(8F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(8F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —N—NH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is hydrogen, halogen, —OCH₃, SO₂, SO₂—R^(9B),—OR^(9A), —NR^(9B)R^(9C) or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is hydrogen. Inembodiments, R⁹ is —Br. In embodiments, R⁹ is —Cl. In embodiments, R⁹ is—SO₂—R^(9B) wherein R^(9B) is substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁹ is —SO₂—R^(9B)wherein R^(9B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁹ is SO₂—R^(9B) wherein R^(9B) is phenyl. Inembodiments, R⁹ is phenyl. In embodiments, R⁹ is —OR^(9A), whereinR^(9A) is substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁹ is —OR^(9A), wherein R^(9A)is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁹ is —OR^(9A), wherein R^(9A) is substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁹ is —OR^(9A), whereinR^(9A) is substituted or unsubstituted C₁-C₄ alkyl. In embodiments, R⁹is —OR^(9A), wherein R^(9A) is substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R⁹ is —NR^(9B)R^(9C), wherein R^(9B) and R^(9C) areunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁹ is —NR^(9B)R^(9C), wherein R^(9B) and R^(9C) aresubstituted or unsubstituted C₁-C₈ alkyl. In embodiments, R⁹ is—NR^(9B)R^(9C), wherein R^(9B) and R^(9C) are substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁹ is —NR^(9B)R^(9C), whereinR^(9B) and R^(9C) are substituted or unsubstituted C₁-C₂ alkyl.

R⁹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R⁹ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R⁹ may be halogen, substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). R⁹ may behalogen, or substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). R⁹ may be halogen, or unsubstituted alkyl (e.g.,C₁—C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R⁹ may be halogen, orsubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R⁹ may be halogen, unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl. R⁹ may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R⁹ may behydrogen.

R⁹ may be hydrogen, R^(9E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(9E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(9E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), R^(9E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(9E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(9E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R⁹ may be R^(9E)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(9E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(9E)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(9E)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl), R^(9E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), orR^(9E)-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁹ is R^(9E)-substitutedalkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R⁹ is anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁹ is R^(9E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R⁹ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R⁹ isR^(9E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).In embodiments, R⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,or C₅-C₆ cycloalkyl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁹ is R^(9E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁹ is R^(9E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁹ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R⁹ is R^(9E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R⁹ is R^(9E)-substituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R⁹ is an unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(9E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(9F)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R^(9F)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(9F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(9F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(9F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(9F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(9F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is hydrogen, halogen, —OCH₃, —SO₂, —SO₂—R^(10B),OR^(10A), —NR^(10B)R^(10C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is hydrogen. Inembodiments, R¹⁰ is —Br. In embodiments, R¹⁰ is —Cl. In embodiments, R¹⁰is —SO₂—R^(10B) wherein R^(10B) is substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is—SO₂—R^(10B) wherein R^(10B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is —SO₂—R^(10B) whereinR^(10B) is phenyl. In embodiments, R¹⁰ is phenyl. In embodiments, R¹⁰ is—OR^(10A), wherein R^(10A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is—OR^(10A), wherein R^(10A) is unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is —OR^(10A), whereinR^(10A) is substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R¹⁰is —OR^(10A), wherein R^(10A) is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R¹⁰ is —OR^(10A), wherein R^(10A) is substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁰ is —NR^(10B)R^(10C),wherein R^(10B) and R^(10C) are unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ is —NR^(10B)R^(10C),wherein R^(10B) and R^(10C) are substituted or unsubstituted C₁-C₈alkyl. In embodiments, R¹⁰ is —NR^(10B)R^(10C) wherein R^(10B) andR^(10C) are substituted or unsubstituted C₁-C₄ alkyl. In embodiments,R¹⁰ is —NR^(10B)R^(10C), wherein R^(10B) and R^(10C) are substituted orunsubstituted C₁-C₂ alkyl.

R¹⁰ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹⁰ may be halogen, substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). R¹⁰ may behalogen, or substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). R¹⁰ may be halogen, or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R¹⁰ may be halogen, orsubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R¹⁰ may be halogen, unsubstituted heteroalkyl (e.g., 2 to8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl. R¹⁰ may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R¹ may behydrogen.

R¹⁰ may be hydrogen, R^(10E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(10E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(1E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(10E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(10E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(10E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁰ may be R^(10E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(10E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(10E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(10E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(10E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(10E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁰ isR^(10E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁰ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁰ is R^(10E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁰ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁰ isR^(10E)-substituted cycloalkyl (e.g., C₃-C₈, C₃—C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁰ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁰ is R^(10E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁰ is R^(0E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁰ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁰ is R^(10E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁰ is R^(10E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁰ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(10E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(10F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(10F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(10F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(10F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(1F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(10F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(10F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁—C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹¹ is hydrogen, halogen, —OCH₃, —SO₂, —SO₂—R^(11B),OR^(11A), —NR^(11B)R^(11C), or substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ is hydrogen. Inembodiments, R¹¹ is —Br. In embodiments, R¹¹ is —Cl. In embodiments, R¹¹is —SO₂—R^(11B) wherein R^(11B) is substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹¹ is—SO₂—R^(11B) wherein R^(11B) is unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R¹¹ is —SO₂—R^(11B) whereinR^(11B) is phenyl. In embodiments, R¹¹ is phenyl. In embodiments, R¹¹ is—OR^(11A), wherein R^(11A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ is—OR^(11A), wherein R^(11A) is unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ is —OR^(11A), whereinR^(11A) is substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R¹¹is —OR^(11A), wherein R^(11A) is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R¹¹ is —OR^(11A), wherein R^(11A) is substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹¹ is —NR^(11B)R^(11C),wherein R^(11B) and R^(11C) are unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹¹ is —NR^(11B)R^(11C),wherein R^(11B) and R^(11C) are substituted or unsubstituted C₁-C₈alkyl. In embodiments, R¹¹ is —NR^(11B)R^(11C) wherein R^(11B) andR^(11C) are substituted or unsubstituted C₁-C₄ alkyl. In embodiments,R¹¹ is —NR^(11B)R^(11C), wherein R^(11B) and R^(11C) are substituted orunsubstituted C₁-C₂ alkyl.

R¹¹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹¹ may be halogen, substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). R¹¹ may behalogen, or substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). R¹¹ may be halogen, or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R¹¹ may be halogen, orsubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). R¹¹ may be halogen, unsubstituted heteroalkyl (e.g., 2 to8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl. Rn may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R¹¹ may behydrogen.

R¹¹ may be hydrogen, R^(11E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(11E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(11E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(11E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(11E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(11E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹¹ may be R^(11E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(11E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(11E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(11E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(11E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(11E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹¹ is R^(1E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹¹ isR^(11E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹¹ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹¹ is R^(11E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹¹ is R^(11E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹¹ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹¹ is R^(11E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹¹ isR^(11E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹¹ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹¹ is R^(11E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹¹ is R^(11E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹¹ is R^(11E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹¹ is R^(11E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹¹ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹¹ is R^(11E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹¹ is R^(11E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹¹ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(11E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(11F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(11F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(11F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(11F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(11F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(11F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(11F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R⁹ and R¹⁰ may be joined together to form substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R⁹ and R¹⁰ may be joinedtogether to form substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R⁹ and R¹⁰ may be joined together toform substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁹and R¹⁰ may be joined together to form substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl). R⁹ and R¹⁰ may be joinedtogether to form R^(9E)-substituted or unsubstituted cycloalkyl (e.g. 3to 8 membered cycloalkyl). R⁹ and R¹⁰ may be joined together to formR^(9E)-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl). R⁹ and R¹⁰ may be joined together to formR^(9E)-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁹and R¹⁰ may be joined together to form R^(9E)-substituted orunsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

R¹⁰ and R¹¹ may be joined together to form substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R¹⁰ and R¹¹ may be joinedtogether to form substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R¹⁰ and R¹¹ may be joined together toform substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R¹⁰and R¹¹ may be joined together to form substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl). R¹⁰ and R¹¹ may be joinedtogether to form R^(11E)-substituted or unsubstituted cycloalkyl (e.g. 3to 8 membered cycloalkyl). R¹⁰ and R¹¹ may be joined together to formR^(10E)-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl). R¹⁰ and R¹¹ may be joined together to formR^(10E)-substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl).R¹⁰ and R¹¹ may be joined together to form R^(10E)-substituted orunsubstituted heteroaryl (e.g. 3 to 8 membered heteroaryl).

In embodiments, R⁷, R⁸, R⁹, R¹⁰ and R″ are independently hydrogen,halogen, C₁-C₅ unsubstituted alkyl, 2 to 5 membered unsubstitutedheteroalkyl. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ may independently be hydrogen,halogen, unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹⁰ and R¹¹ may behydrogen.

The compound of formula (II) may have the formula:

The symbol p, X³, X⁴, X⁵, p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,and R¹¹ are as described herein, including embodiments thereof. R⁵ andR⁶ may independently be unsubstituted C₁-C₃ alkyl or unsubstituted 3 to5 membered cycloalkyl. R⁷, R⁸, R⁹, and R¹⁰ may independently behydrogen, halogen, unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹ maybe —CN or unsubstituted 2 to 5 membered heteroalkyl. R¹ may be —CN. R¹may be —COOCH₃. R¹ may be unsubstituted methyl. R² may be C₁-C₃unsubstituted alkyl. When R¹ is —CN, R² may be unsubstituted methyl. R³and R⁴ may be hydrogen. R¹⁰ and R¹¹ may be hydrogen.

The compound of formula (II) may have the formula:

The symbol p, X³, X⁴, X⁵, p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,and R¹¹ are as described herein, including embodiments thereof. R⁵ andR⁶ may independently be unsubstituted C₁-C₃ alkyl or unsubstituted 3 to5 membered cycloalkyl. R⁷, R⁸, R⁹, and R¹⁰ may independently behydrogen, halogen, unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹ maybe —CN or unsubstituted 2 to 5 membered heteroalkyl. R¹ may be —CN. R¹may be —COOCH₃. R¹ may be unsubstituted methyl. R² may be C₁-C₃unsubstituted alkyl. When R¹ is —CN, R² may be unsubstituted methyl. R³and R⁴ may be hydrogen. R¹⁰ and R¹¹ may be hydrogen.

The compound of formula (II) may have the formula:

In embodiments, R⁸ is hydrogen or —OR^(33J). R⁹, R¹⁰, and R¹¹ mayindependently be hydrogen or halogen. R^(33J) may be hydrogen, orunsubstituted alkyl (e.g. unsubstituted methyl, unsubstituted ethyl, orunsubstituted propyl).

The compound of formula (II) may have the formula:

R⁸ may be hydrogen or —OR^(8A). R⁹, R¹⁰, and R¹¹ may independently behydrogen or halogen. R^(8A) may be hydrogen, or unsubstituted alkyl. R⁸may be hydrogen.

The compound of formula (II1) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II2) may have the formula:

The compound of formula (II) may have the formula:

The symbol R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are asdescribed herein, including embodiments thereof.

The compound of formula (II3) may have the formula:

The compound of formula (II) may have the formula:

p is as described herein.

The compound of formula (I) may have the formula:

The symbol p, R¹, R², R³, R⁴, R⁵, R⁶, and R¹⁶ are as described herein,including embodiments thereof. R⁵ and R⁶ may independently beunsubstituted C₁-C₃ alkyl or unsubstituted 3 to 5 membered cycloalkyl.R⁷, R⁸, R⁹, and R¹⁰ may independently be hydrogen, halogen,unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹ may be —CN orunsubstituted 2 to 5 membered heteroalkyl. R¹ may be —CN. R¹ may be—COOCH₃. R¹ may be unsubstituted methyl. R² may be C₁-C₃ unsubstitutedalkyl. When R¹ is —CN, R² may be unsubstituted methyl. R³ and R⁴ may behydrogen. R¹⁰ and R¹¹ may be hydrogen.

X⁶ is —CR^(23A)— or —N═. X⁷ is —CR^(24A)R^(24B), —S—, —O—, or—NR^(24C)—.

R¹⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(19A), —NR^(19B)R^(19C), —COOR^(19A), —CON^(19B)R^(19B)R^(19C),—NO₂, —SR^(19D), SO_(n19)R^(19B), —SO_(v19)NR^(19B)R^(19C),—NHNR^(19B)R^(19C), ONR^(19B)R^(19C), —NHC(O)NHNR^(19B)R^(19C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R²⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(20A), —NR^(20B)R^(20C), COOR^(20A), CONR^(20B)R^(20C), —NO₂,—SR^(20D), —SO_(n20)R^(20B), —SO_(v20)NR^(20B)R^(20C),—NHNR^(20B)R^(20C), —ONR^(20B)R^(20C), NHC(O)N—NR^(20B)R^(20C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C) andR^(20D) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. n19 and n20 are independently 1or 4. v19, and v20 are independently 1 or 2. X is —F, —Cl, —Br, or —I.

R¹⁹ and R²⁰ may optionally be bonded together to form R^(19E)—substituted or unsubstituted 3 to 6 membered cycloalkyl, R^(19E)—substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R^(19E)—substituted or unsubstituted phenyl, or R^(19E)-substituted orunsubstituted 5 to 6 membered heteroaryl.

R^(23A), R^(24A), and R^(24B) are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R^(24C) is hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. X is —F,—Cl, —Br, or —I.

R^(23A), R^(24A), R^(24B) and R^(24C) may be independently hydrogen,R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl), R³⁴substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl), R³⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). R^(23A),R^(24A), R^(24B) and R^(24C) may be independently R³⁴-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, or 2 to 4 membered heteroalkyl), R³⁴-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R³⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl). In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) areindependently R³⁴-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl). In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) areindependently an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, or 2 to 4 membered heteroalkyl). In embodiments, R^(23A),R^(24A), R^(24B) and R^(24C) are independently R³⁴-substitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) areindependently an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, orC₅-C₆ cycloalkyl). In embodiments, R^(23A)R^(24A), R^(24B) and R^(24C)are independently R³⁴-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, orC₅-C₆ cycloalkyl). In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C)are independently an unsubstituted cycloalkyl (e.g., C₃-C₅, C₃-C₆, orC₅-C₆ cycloalkyl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl). Inembodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, or 5 to 6 membered heterocycloalkyl). In embodiments, R^(23A),R^(24A), R^(24B) and R^(24C) are independently an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). Inembodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments,R^(23A), R^(24A), R^(24B) and R^(24C) are independently an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) are independentlyR³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl). In embodiments, R^(23A),R^(24A), R^(24B) and R^(24C) are independently R³⁴-substitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R^(23A), R^(24A), R^(24B) and R^(24C) areindependently an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered heteroaryl).

R³⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N—₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(34F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(34F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(34F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(34F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(34F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(34F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(34F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹⁹ and R^(24A) may optionally be bonded together to formR³⁴-substituted or unsubstituted 3 to 6 membered cycloalkyl,R³⁴-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R³⁴-substituted or unsubstituted phenyl, or R³⁴-substituted orunsubstituted 5 to 6 membered heteroaryl. R²⁰ and R^(23A) may optionallybe bonded together to form R³⁴-substituted or unsubstituted 3 to 6membered cycloalkyl, R³⁴-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, R³⁴-substituted or unsubstituted phenyl, orR³⁴-substituted or unsubstituted 5 to 6 membered heteroaryl.

When X⁷ is —S—, X⁶ may be —N═ or —CR^(23A)═. When X⁷ is —NH—, X⁶ may be—N— or —CR^(23A)═. When X⁷ is NR^(24C)—, X⁶ may —CR^(23A)═ or —N═. WhenX⁷ is —O═, X⁶ may be —N═, —CH═, or —CR^(23A)═. In certain embodiments,X⁷ is —S— and X⁶ is —CH═. p may be 2, 3, or 4. In certain embodiments pis 2.

R¹⁹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₁-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹⁹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —S₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(19E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), orR^(19E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl). R⁹ may be halogen,substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl). R¹⁹ may be halogen, orsubstituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R¹⁹ may be halogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl). R¹⁹ may be halogen, or substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). R¹⁹ may be halogen, unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl. R¹⁹ may behalogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R¹⁹ may be hydrogen.

R¹⁹ may be hydrogen, R^(19E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(19E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(19E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), R^(19E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(19E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(19E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁹ may be R^(19E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(19E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(19E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(19E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(19E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(19E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstituted alkyl(e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁹ isR^(19E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁹ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁹ is R^(19E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁹ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁹ isR^(19E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁹ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁹ is R^(19E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁹ is R^(19E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁹ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁹ is R^(19E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁹ is R^(19E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁹ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(19E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(19F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(19F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(19F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(19F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(19F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(19F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(19F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₁-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R²⁰ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R²⁰ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or2 to 4 membered heteroalkyl). R²⁰ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R²⁰ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R²⁰ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R²⁰ may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R²⁰ maybe halogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R²⁰ may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R²⁰ may be hydrogen.

R²⁰ may be hydrogen, R^(20E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(20E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(20E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(20E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(20E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(20E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R²⁰ may be R^(20E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(20E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(20E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(20E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(20E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(20E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R²⁰ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂C₁, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(20E)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), or R^(20E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R²⁰ isR^(20E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R²⁰ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R²⁰ is R^(20E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R²⁰ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R²⁰ isR^(20E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R²⁰ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R²⁰ is R^(20E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R²⁰ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R²⁰ is R^(20E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R²⁰ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R²⁰ is R^(20E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R²⁰ is R^(20E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R²⁰ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(20E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(20F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(20F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(20F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(20F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(20F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(20F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(20F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

The compound of formula (III) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (III1) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (I) may have the formula:

The symbol p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, and R¹⁶ are asdescribed herein, including embodiments thereof.

X¹ is —CR^(21A)R^(21B), —O—, —NR^(21C), or —S—. X² is —CR^(22A)R^(22B)—,—O—, —NR^(22C)—, or —S—.

R^(21A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(21A) is hydrogen.

R^(21B) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(21B) is hydrogen.

R^(21C) is hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). X is independently —F, —Cl, —Br, or —I. In embodiments,R^(21C) is hydrogen.

R^(22A) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(22A) is hydrogen.

R^(22B) is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(22B) is hydrogen.

R^(22C) is hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). X is independently —F, —Cl, —Br, or —I. In embodiments,R^(22C) is hydrogen.

R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(12A), —NR^(12B)R^(12C), —COOR^(12A), —CONR^(12B)R^(12C), —NO₂,—SR^(12D), —SO_(n12)R^(12B), —SO_(v12)NR^(12B)R^(12C),—NHNR^(12B)R^(12C), ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₅cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), CONR^(13B)R^(13C), —NO₂,—SR^(13D), —SO_(n13)R^(13B), SO_(v13)NR^(13B)R^(13C),—NHNR^(13B)R^(13C), —ONR^(13B)R^(13C), —NHC(O)N—R^(13B)R^(13C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R¹⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(14A), —NR^(14B)R^(14C), —COOR^(14A), CONR^(14B)R^(14C), —NO₂,—SR^(14D), SO_(n14)R^(14B), SO_(v14)NR^(14B)R^(14C), —NHNR^(14B)R^(14C),—ONR^(14B)R^(14C), —NHC(O)NHNR^(14B)R^(14C), substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R¹⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(15A), —NR^(15B)R^(15C), —COOR^(15A), CONR^(15B)R^(15C), —NO₂,—SR^(15D), —SO_(n15)R^(15B), —SO_(v15)NR^(15B)R^(15C),—NHNR^(15B)R^(15C), ONR^(15B)R^(15C), —NHC(O)NHNR^(15B)R^(15C),substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D),R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B), R^(15C), andR^(15D) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R⁵ and R⁶ may independently be unsubstituted C₁-C₃ alkyl orunsubstituted 3 to 5 membered cycloalkyl. R⁷, R⁸, R⁹, and R¹⁰ mayindependently be hydrogen, halogen, unsubstituted methyl, —OCH₃ or—O(CH₂)₂═CH₂. R¹ may be —CN or unsubstituted 2 to 5 memberedheteroalkyl. R¹ may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstitutedmethyl. R² may be C₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may beunsubstituted methyl. R³ and R⁴ may be hydrogen. R¹⁰ and R¹¹ may behydrogen. R¹², R¹³, R¹⁴, and R¹⁵ may be hydrogen.

R^(21A), R^(21B), R^(22A), and R^(22B) are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R³⁴-substitutedor unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

R^(21C) and R^(22C) are independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, R³⁴-substituted or unsubstituted alkyl (e.g.,C₁-C₅ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁴-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R³⁴-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R³⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁴-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X is independently —F, —Cl, —Br, or —I.

R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) may beindependently hydrogen, substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered heteroaryl). R^(21A), R^(21B), R^(22A),R^(22B), and R^(22C) may be independently substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). R^(21A), R^(21B), R^(22A), and R^(22B) may beindependently hydrogen, halogen, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), or substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). R^(21A)R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) maybe independently hydrogen, or substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R^(21A)R^(21B), R^(21C), R^(22A),R^(22B), and R^(22C) may be independently hydrogen, or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R^(21A), R^(21B), R^(21C),R^(22A), R^(22B), and R^(22C) may be independently hydrogen, orsubstituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl). R^(21A), R^(21B), R^(21C),R^(22A), R^(22B), and R^(22C) may be independently hydrogen, orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl. R^(21A), R^(21B), R^(21C), R^(22A), R^(22B),and R^(22C) may be independently hydrogen, —CF₃, —CCl₃, —CBr₃, or —CI₃.

R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) may beindependently hydrogen, R³⁴-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R³⁴-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), R³⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R³⁴-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or R³⁴-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R^(21A), R^(21B), R^(21C), R^(22A), R^(22B) and R^(22C) maybe independently R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), R³⁴-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), R³⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R³⁴-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or R³⁴-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl).

In embodiments, R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl). In embodiments, R^(21A), R^(21B), R^(21C),R^(22A), R^(22B), and R^(22C) are independently R³⁴-substituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R^(21A), R^(21B),R^(21C), R^(22A), R^(22B), and R^(22C) are independently anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).

In embodiments, R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). Inembodiments, R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted heteroalkyl (e.g., 2 to 8 membered, 2to 6 membered, or 2 to 4 membered heteroalkyl). In embodiments, R^(21A),R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) are independently anunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl).

In embodiments, R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R^(21A), R^(21B),R^(21C), R^(22A), R^(22B), and R^(22C) are independently R³⁴-substitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments,R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) areindependently an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl).

In embodiments, R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 memberedheterocycloalkyl). In embodiments, R^(21A), R^(21B), R^(21C), R^(22A),R^(22B), and R^(22C) are independently R³⁴-substituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 memberedheterocycloalkyl). In embodiments, R^(21A), R^(21B), R^(21C), R^(22A),R^(22B), and R^(22C) are independently an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 memberedheterocycloalkyl).

In embodiments, R^(21A)R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀,C₁₀, or phenyl). In embodiments, R^(21A), R^(21B), R^(21C), R^(22A),R^(22B), and R^(22C) are independently R³⁴-substituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^(21A), R^(21B), R^(21C),R^(22A), R^(22B), and R^(22C) are independently an unsubstituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R^(21A)R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C)are independently R³⁴-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl). Inembodiments, R^(21A)R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) areindependently R³⁴-substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered heteroaryl). In embodiments, R^(21A),R^(21B), R^(21C), R^(22A), R^(22B), and R^(22C) are independently anunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(21A), R^(21B), R^(21C), R^(22A), R^(22B), and/or R^(22C) may be fusedto form R³⁴-substituted or unsubstituted 5 or 6 memberedheterocycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted 5 or 6 membered heteroaryl. R^(21C) andR^(22C) are independently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, R³⁴-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁴-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³⁴-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₁-C₆ cycloalkyl), R³⁴-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁴-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR³⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

n12, n13, n14 and n15 are independently 1 or 4. v12, v13, v14, and v15are independently 1 or 2.

R¹² may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹² may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or2 to 4 membered heteroalkyl). R¹ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R¹ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R¹² may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R¹² may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹² maybe halogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R¹² may be halogen, —CF₃,—CCl₃, —CBr₃, or —CI₃. R¹² may be hydrogen.

R¹² may be hydrogen, R^(12E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(12E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(12E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(12E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(2E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(12E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹ may be R^(12E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(2E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(12E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(12E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(2E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(12E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹² is R^(12E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹² isR^(12E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹² is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹² is R^(12E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹² is R^(12E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹² is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹² is R^(12E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹² isR^(12E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹² is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹² is R^(12E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹ is R^(12E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹² is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹² is R^(12E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹ is R^(12E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹² is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹² is R^(12E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹² is R^(12E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹² is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(12E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(12F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(12F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(12F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(12F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(2F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(12F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(12F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₁-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹³ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹³ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or2 to 4 membered heteroalkyl). R¹ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R¹³ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R¹³ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R¹³ may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹³ maybe halogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R¹³ may be halogen, —CF₃,—CCl₃, —CBr₃, or —C₃. R¹³ may be hydrogen.

R¹³ may be hydrogen, R^(13E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(13E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(13E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(13E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(13E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(13E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R³ may be R^(13E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(13E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(13E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(13E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(13E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(13E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹³ is R^(13E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹³ isR^(13E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹³ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹³ is R^(13E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹³ is R^(13E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹³ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹³ is R^(13E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹³ isR^(13E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹³ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹³ is R^(13E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹³ is R^(13E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹³ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹³ is R^(13F)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹³ is R^(13E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹³ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹³ is R^(13E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹³ is R^(13E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹³ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(13E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(13F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(13F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(13F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(13F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(13F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(13F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(13F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹⁴ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —S₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered heteroaryl). R¹⁴ may be halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹⁴may be halogen, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹⁴ may behalogen, or substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, orC₁-C₄ alkyl). R¹⁴ may be halogen, or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, or C₁-C₄ alkyl). R¹⁴ may be halogen, or substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R¹⁴ may be halogen, unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl. R¹⁴ may be halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃. R¹⁴ may behydrogen.

R¹⁴ may be hydrogen, R^(14E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(14E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(14E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(14E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(14E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(14E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁴ may be R^(14E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(14E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(14E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(14E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(14E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(14E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁴ isR^(14E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁴ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁴ is R^(14E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁴ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁴ isR^(14E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁴ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁴ is R^(14E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁴ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁴ is R^(14E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁴ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁴ is R^(14E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁴ is R^(14E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁴ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(14E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(14F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(14F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(14F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(14F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(14F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(14F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(14F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₁-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R¹⁵ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,

R¹⁵ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —N₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀ aryl, or phenyl), or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R¹⁵ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or2 to 4 membered heteroalkyl). R¹⁵ may be halogen, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl). R¹⁵ may be halogen, or substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). R¹⁵ may behalogen, or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl).R¹⁵ may be halogen, or substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl). R¹⁵ maybe halogen, unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl. R¹⁵ may be halogen, —CF₃,—CCl₃, —CBr₃, or —C₃. R¹⁵ may be hydrogen.

R¹⁵ may be hydrogen, R^(15E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(15E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(15E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(15E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(15E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(15E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl). R¹⁵ may be R^(15E)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl),R^(15E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, or 2 to 4 membered heteroalkyl), R^(15E)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl),R^(15E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, or 5 to 6 membered heterocycloalkyl),R^(15E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀ aryl, orphenyl), or R^(15E)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). In embodiments, R¹⁵ isR^(15E)-substituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl). Inembodiments, R¹⁵ is an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹ is R^(15E)-substituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁵ is an unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl). In embodiments, R¹⁵ isR^(15E)-substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆cycloalkyl). In embodiments, R¹⁵ is an unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹ is R^(15E)-substitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹ is R^(15E)-substituted aryl(e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁵ is an unsubstitutedaryl (e.g., C₆-C₁₀, C₁₀, or phenyl).

In embodiments, R¹⁵ is R^(15E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁵ is R^(15E)-substituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁵ is an unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered heteroaryl).

R^(15E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(15F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(15F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(15F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(15F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(15F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(15F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(15F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OC₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

The compound of formula (IV) may have the formula:

The symbol p, X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³,R¹⁴ and R¹⁵ are as described herein, including embodiments thereof.

The compound of formula (IV) may have the formula:

The symbol X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴and R¹⁵ are as described herein, including embodiments thereof.

The compound of formula (IV1) may have the formula:

The compound of formula (IV1) may have the formula:

The symbol R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵are as described herein, including embodiments thereof.

The compound of formula (IV2) may have the formula:

The compound of formula (IV2) may have the formula:

In some embodiments, the compound of formula (I) has the structure offormula (V):

The symbol X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², and R¹³are as described herein, including embodiments thereof.

In some embodiments, R⁵ and R⁶ are independently unsubstituted C₁-C₃alkyl or unsubstituted 3 to 5 membered cycloalkyl. In some embodiments,R⁷, R¹⁰, and R¹¹ and independently hydrogen, halogen, unsubstitutedmethyl, —OCH₃ or —O(CH₂)₂═CH₂. In some embodiments, R¹ is —CN orunsubstituted 2 to 5 membered heteroalkyl. In some embodiments, R¹ is—CN. In some embodiments, R¹ is —COOCH₃. In some embodiments, R¹ isunsubstituted methyl. In some embodiments, R² is C₁-C₃ unsubstitutedalkyl. In some embodiments, when R¹ is —CN, R² may be unsubstitutedmethyl. In some embodiments, R³ and R⁴ are hydrogen. In someembodiments, R¹⁰ and R¹¹ are hydrogen. In some embodiments, R¹² and R¹³are hydrogen.

In some embodiments, the compound of formula (V) has the structure offormula (V(S)):

In some embodiments of a compound of formula (V (S)), X¹ and X² areindependently O or S. In some embodiments of a compound of formula (V(S)), p is 2. In some embodiments of a compound of formula (V (S)), p is3.

In some embodiments, the compound of formula (V) has the structure offormula (V(R)):

In some embodiments of a compound of formula (V(R)), X¹ and X² areindependently O or S. In some embodiments of a compound of formula(V(R)), p is 2. In some embodiments of a compound of formula (V(R)), pis 3.

In some embodiments, the compound of formula (V) has the structure offormula (V1):

In some embodiments, the compound of formula (VI) has the structure offormula (V-1(S)):

In some embodiments, the compound of formula (VI) has the structure offormula (V-1(R)):

In some embodiments, the compound of formula (VI) has the structure offormula (V2):

In some embodiments of a method of treating T-cell lymphoma, thecompound of formula (V2(S)) has the structure of formula (V2(S)):

In some embodiments of a compound of formula (V2(S)), R¹ is —CN,—OR^(1A), —COOR^(1A), or —CONR^(1B)R^(1C), wherein R^(1A), R^(1B), andR^(1C) are independently hydrogen, or substituted or unsubstitutedalkyl. In some embodiments of a compound of formula (V2(S)), R¹ is —CN.In some embodiments of a compound of formula (V2(S)), R² is —CF₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl. In some embodiments of a compound offormula (V2(S)), R² is substituted or unsubstituted alkyl or substitutedor unsubstituted heteroalkyl. In some embodiments of a compound offormula (V2(S)), R² is methyl. In some embodiments of a compound offormula (V2(S)), R³ and R⁴ are independently hydrogen. In someembodiments of a compound of formula (V2(S)), R¹² and R¹¹ areindependently hydrogen. In some embodiments of a compound of formula(V2(S)), R¹⁰ and R¹¹ are independently hydrogen.

In some embodiments, the compound of formula (V1(R)) has the structureof formula (V2(R)):

In some embodiments of a compound of formula (V2(R)), R¹ is —CN,—OR^(1A), —COOR^(1A), or —CONR^(1B)R^(1C), wherein R^(1A), R^(1B), andR^(1C) are independently hydrogen, or substituted or unsubstitutedalkyl. In some embodiments of a compound of formula (V2(R)), R¹ is —CN.In some embodiments of a compound of formula (V2(R)), R² is —CF₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl. In some embodiments of a compound offormula (V2(R)), R² is substituted or unsubstituted alkyl or substitutedor unsubstituted heteroalkyl. In some embodiments of a compound offormula (V2(R)), R² is methyl. In some embodiments of a compound offormula (V2(R)), R³ and R⁴ are independently hydrogen. In someembodiments of a compound of formula (V2(R)), R¹² and R¹¹ areindependently hydrogen. In some embodiments of a compound of formula(V2(R)), R¹⁰ and R¹¹ are independently hydrogen.

In some embodiments, the compound of formula (V) may have the structureof formula:

In some embodiments, the compound of formula (V) may have the structureof formula:

In some embodiments, the compound of formula (V) has the structure offormula (V3):

In some embodiments, the compound of formula (V3) may have the structureof formula (V3(S)):

In some embodiments, the compound of formula (V3) may have the structureof formula (IV(R)):

The compound of formula (VI) may have the formula:

The compound of formula (V4) may have the formula:

In some embodiments, the compound of formula (V4) may have the structureof formula:

The compound of formula (I) may have the formula:

The symbols X¹, X², p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, andR¹⁶ are as described herein, including embodiments thereof.

R⁵ and R⁶ may independently be unsubstituted C₁-C₃ alkyl orunsubstituted 3 to 5 membered cycloalkyl. R⁷, R⁸, and R⁹ mayindependently be hydrogen, halogen, unsubstituted methyl, —OCH₃ or—O(CH₂)₂═CH₂. R¹ may be —CN or unsubstituted 2 to 5 memberedheteroalkyl. R¹ may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstitutedmethyl. R² may be C₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may beunsubstituted methyl. R³ and R⁴ may be hydrogen. R⁷ and R⁸ may behydrogen. R¹² and R¹³ may be hydrogen. R⁷, R⁸, and R⁹ may be hydrogen.

The compound of formula (VI) may have the formula:

The compound formula (VI) may have the formula:

The compound of formula (VI1) may have the formula:

The compound of formula (VI) may have the formula:

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D),R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D),R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B), R^(15C), R^(15D),R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), R^(18D),R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C), R^(20D),R^(21C), R^(22C), and R^(24C) are independently hydrogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D),R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D),R^(14A), R^(14B), R^(14C), R^(14D), R^(15A), R^(15B), R^(15C), R^(15D),R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), R^(18D),R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C), R^(20D),R^(21C), R^(22C), and R^(24C) are independently hydrogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, R³⁴-substituted or unsubstituted alkyl,R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted orunsubstituted cycloalkyl, R³⁴-substituted or unsubstitutedheterocycloalkyl, R³⁴-substituted or unsubstituted aryl, orR³⁴-substituted or unsubstituted heteroaryl. R^(1A), R^(1B), R^(1C),R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D),R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A),R^(6B), R^(6C), R^(6D), R^(7A)R^(7B)R^(7C), R^(7D), R^(8A),R^(8B)R^(8C), R^(8D), R^(9A), R^(9B)R^(9C), R^(9D), R^(11A), R^(11B),R^(11C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(12A), R^(12B),R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D), R^(14A), R^(14B),R^(14C), R^(14D), R^(15A), R^(15B), R^(15C), R^(15D), R^(16A), R^(16B),R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), R^(18D), R^(19A), R^(19B),R^(19C), R^(19D), R^(20A), R^(20B), R^(20C), R^(20D)D, R^(21C), R^(22C),and R^(24C) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is3. In embodiments, n1 is 4. In embodiments, n2 is 1. In embodiments, n2is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments,n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3. Inembodiments, n3 is 4. In embodiments, n4 is 1. In embodiments, n4 is 2.In embodiments, n4 is 3. In embodiments, n4 is 4. In embodiments, n5is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments,n5 is 4. In embodiments, n6 is 1. In embodiments, n6 is 2. Inembodiments, n6 is 3. In embodiments, n6 is 4. In embodiments, n7 is 1.In embodiments, n7 is 2. In embodiments, n7 is 3. In embodiments, n7 is4. In embodiments, n8 is 1. In embodiments, n8 is 2. In embodiments, n8is 3. In embodiments, n8 is 4. In embodiments, n9 is 1. In embodiments,n9 is 2. In embodiments, n9 is 3. In embodiments, n9 is 4. Inembodiments, n10 is 1. In embodiments, n10 is 2. In embodiments, n10 is3. In embodiments, n10 is 4. In embodiments, n11 is 1. In embodiments,n11 is 2. In embodiments, n11 is 3. In embodiments, n11 is 4. Inembodiments, n12 is 1. In embodiments, n12 is 2. In embodiments, n12 is3. In embodiments, n12 is 4. In embodiments, n13 is 1. In embodiments,n13 is 2. In embodiments, n13 is 3. In embodiments, n13 is 4. Inembodiments, n14 is 1. In embodiments, n14 is 2. In embodiments, n14 is3. In embodiments, n14 is 4. In embodiments, n15 is 1. In embodiments,n15 is 2. In embodiments, n15 is 3. In embodiments, n15 is 4. Inembodiments, n16 is 1. In embodiments, n16 is 2. In embodiments, n16 is3. In embodiments, n16 is 4. In embodiments, n19 is 1. In embodiments,n19 is 2. In embodiments, n19 is 3. In embodiments, n19 is 4. Inembodiments, n20 is 1. In embodiments, n20 is 2. In embodiments, n20 is3. In embodiments, n20 is 4.

In embodiments, v1 is 1. In embodiments, v is 2. In embodiments, v2is 1. In embodiments, v2 is 2. In embodiments, v3 is 1. In embodiments,v3 is 2. In embodiments, v4 is 1. In embodiments, v4 is 2. Inembodiments, v5 is 1. In embodiments, v5 is 2. In embodiments, v6 is 1.In embodiments, v6 is 2. In embodiments, v7 is 1. In embodiments, v7 is2. In embodiments, v8 is 1. In embodiments, v8 is 2. In embodiments, v9is 1. In embodiments, v9 is 2. In embodiments, v10 is 1. In embodiments,v10 is 2. In embodiments, v11 is 1. In embodiments, v11 is 2. Inembodiments, v12 is 1. In embodiments, v12 is 2. In embodiments, v3is 1. In embodiments, v13 is 2. In embodiments, v14 is 1. Inembodiments, v4 is 2. In embodiments, v15 is 1. In embodiments, v15 is2. In embodiments, v is 16. In embodiments, v16 is 2. In embodiments, vis 18. In embodiments, v8 is 2. In embodiments, v19 is 1. Inembodiments, v9 is 2. In embodiments, v20 is 1. In embodiments, v20 is2.

Non-Bridged Forms of Compounds

In an aspect is provided a compound (ETP compound) for use in themethods provided herein having the formula (XXI):

or a pharmaceutically acceptable salt thereof. R¹, R², R³, R⁴, R⁵, R⁶,R¹⁶, R¹⁸, R²⁵ and R²⁶ are as described above.

In embodiments, R⁶ is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(6A), —CONR^(6B)R^(6C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁶ is substituted or unsubstituted C₁-C₃ alkyl. Inembodiments, R⁶ is s unsubstituted C₁-C₃ alkyl. In embodiments, R⁶ ismethyl.

In embodiments, R⁵ is substituted or unsubstituted C₁-C₃ alkyl. Inembodiments, R⁵ is s unsubstituted C₁-C₃ alkyl. In embodiments, R⁵ ismethyl.

In embodiments, R² is —C(O)-L¹-R³² or —C(S)-L¹-R³². In embodiments, R²⁶is —C(O)-L²-R³³ or —C(S)-L²-R³³. In embodiments, R²⁵ and R²⁶ are joinedto form:

In embodiments, L¹ is a bond, —O—, —NH—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene. In embodiments,L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. In embodiments, R²⁵ and R²⁶are joined to form:

In embodiments, R³² and R³³ are independently hydrogen, halogen, OH,substituted or unsubstituted alkyl, substituted or unsubstituted aryl.In embodiments, R³² and R³³ are independently halogen, OH, substitutedor unsubstituted alkyl, substituted or unsubstituted aryl. Inembodiments, R³² is hydrogen. In embodiments, R³² is halogen. Inembodiments, R³² is —OH. In embodiments, R³² is substituted orunsubstituted alkyl. In embodiments, R³² is substituted or unsubstitutedC₁-C₃ alkyl. In embodiments, R³² is unsubstituted C₁-C₃ alkyl. Inembodiments, R³² is substituted or unsubstituted phenyl. In embodiments,R³² is unsubstituted phenyl. In embodiments, R³³ is hydrogen. Inembodiments, R³³ is halogen. In embodiments, R³³ is —OH. In embodiments,R³³ is substituted or unsubstituted alkyl. In embodiments, R³³ issubstituted or unsubstituted C₁-C₃ alkyl. In embodiments, R³³ isunsubstituted C₁-C₃ alkyl. In embodiments, R³³ is substituted orunsubstituted phenyl. In embodiments, R³³ is unsubstituted phenyl.

In embodiments, R³² and R³³ are independently halogen. In embodimentsR³² and R³ are independently —Cl. In embodiments R³² and R³³ areindependently —OH. In embodiments, R³² and R³³ are independentlysubstituted or unsubstituted C₁-C₃ alkyl or substituted or unsubstitutedaryl. In embodiments, R³² and R³³ are independently unsubstituted C₁-C₃alkyl or unsubstituted aryl.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R¹⁸ is hydrogen.

In embodiments, the compound has the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁶, R¹⁶, R²⁵ and R²⁶ are as described herein.

In embodiments, Ring A is a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, Ring A is substituted or unsubstituted phenyl, substitutedor unsubstituted pyridyl, substituted or unsubstituted pyrazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedoxazolyl, substituted or unsubstituted isoxazolyl, substituted orunsubstituted thiazolyl, substituted or unsubstituted furanyl,substituted or unsubstituted pyrrolyl, or substituted or unsubstitutedthienyl. In embodiments, Ring A is substituted or unsubstituted phenyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

In embodiments, Ring A is a R³⁵-substituted or unsubstituted cycloalkyl,R³⁵-substituted or unsubstituted heterocycloalkyl, R³⁵-substituted orunsubstituted aryl, or R³⁵-substituted or unsubstituted heteroaryl. Inembodiments, Ring A is a R³⁵-substituted cycloalkyl, R³⁵-substitutedheterocycloalkyl, R³⁵-substituted aryl, or R³⁵-substituted heteroaryl.In embodiments, Ring A is a unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted phenyl,R³⁵-substituted or unsubstituted pyridyl, R³⁵-substituted orunsubstituted pyrazolyl, R³⁵-substituted or unsubstituted imidazolyl,R³⁵-substituted or unsubstituted oxazolyl, R³⁵-substituted orunsubstituted isoxazolyl, R³⁵-substituted or unsubstituted thiazolyl,R³⁵-substituted or unsubstituted furanyl, R³⁵-substituted orunsubstituted pyrrolyl, or R³⁵-substituted or unsubstituted thienyl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted pyridinyl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted pyridazinyl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted pyrimidinyl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted pyrazinyl. Inembodiments, Ring A is R³⁵-substituted or unsubstituted triazinyl. Inembodiments, Ring A is R³⁵-substituted phenyl, R³⁵-substituted pyridyl,R³⁵-substituted pyrazolyl, R³⁵-substituted imidazolyl, R³⁵-substitutedoxazolyl, R³⁵-substituted isoxazolyl, R³⁵-substituted thiazolyl,R³⁵-substituted furanyl, R³⁵-substituted pyrrolyl, or R³⁵-substitutedthienyl. In embodiments, Ring A is R³⁵-substituted pyridinyl. Inembodiments, Ring A is R³⁵-substituted pyridazinyl. In embodiments, RingA is R³⁵-substituted pyrimidinyl. In embodiments, Ring A isR³⁵-substituted pyrazinyl. In embodiments, Ring A is R³⁵-substitutedtriazinyl. In embodiments, Ring A is unsubstituted phenyl, unsubstitutedpyridyl, unsubstituted pyrazolyl, unsubstituted imidazolyl,unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstitutedthiazolyl, unsubstituted furanyl, unsubstituted pyrrolyl, orunsubstituted thienyl. In embodiments, Ring A is unsubstitutedpyridinyl. In embodiments, Ring A is unsubstituted pyridazinyl. Inembodiments, Ring A is unsubstituted pyrimidinyl. In embodiments, Ring Ais unsubstituted pyrazinyl. In embodiments, Ring A is unsubstitutedtriazinyl.

R³⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(35F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(35F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(35F)-substituted or unsubstituted cycloalkyl(e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(35F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(35F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(35F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(35F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R²⁵ and R²⁶ areas described herein.

In embodiments, X³ is —N═ or —CR⁷═. In embodiments, X⁴ is —N═ or —CR⁸═.In embodiments, X⁵ is —N═ or —CR⁹═. R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are asdescribed herein. In embodiments, X³ is —CR⁷═ and X⁵ is —CR⁹═. Inembodiments, X³ is —CR⁷═; X⁴ is —N═; X⁵ is —CR⁹═; R¹⁰, R¹¹ and R⁷ areindependently hydrogen; and R⁹ is —OCH₃.

In embodiments, R⁷ and R⁸ may optionally be joined to forma substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl. In embodiments, R⁸ and R⁹ may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl.

In embodiments, R^(7B) and R^(7C), R^(8B) and R^(8C), R^(9B) and R^(9C),R^(10B) and R^(10C), and R^(11B) and R^(11C), substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

As described above, the symbols n6, n7, n8, n9, n10 and n11 areindependently an integer from 1 to 4. Each occurrence of v6, v7, v8, v9,v10 and v11 is independently 1 or 2.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵, R²⁶, X³, X⁴ and X⁵ are asdescribed herein.

In embodiments, R⁷ and R⁸ or R⁸ and R⁹ are optionally joined to form asubstituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁷ and R⁸ or R⁸ and R⁹ are optionally joined to form asubstituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)— or —S—. X² is—CR^(22A)R^(22B)—, —O—, NR^(22C)—, or —S—. The symbol z5 is an integerfrom 0 to 8. The symbol m is 1 or 2. R¹², R¹³, R^(21A), R^(21B),R^(21C), R^(22A), R^(22B), and R^(22C) are as described herein.

In embodiments, X¹ is —O—, —NR^(21C)—, or S. In embodiments, X² is —O—,—NR^(22C)—, or S. In embodiments, m is 1 and z5 is an integer from 0 to6. In embodiments, m is 2 and z5 is an integer from 0 to 8. Inembodiments, z5 is 0.

R²⁷ is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(27A),—NR^(27B)R^(27C), —COOR^(27A), —CONR^(27B)R^(27C), —NO₂, —SR^(27D),SO_(n27)R^(27B), —SO_(v27)NR^(27B)R^(27C), —NHNR^(27B)R^(27C),—ONR^(27B)R^(27C), —NHC(O)NHNR^(27B)R^(27C), substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R²⁷ is halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(27E)-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R^(27E)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R^(27E)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R^(27E)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), R^(27E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(27E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(27E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(27E)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(27E)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(27E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(27E)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁷ isR^(27E)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R²⁷ is an unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁷ is R^(27E)-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁷ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁷ is R^(27E)-substituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁷is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R²⁷ is R^(27E)-substituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R²⁷ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁷ isR^(27E)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁷ is R^(27E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁷ is R^(27E)-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁷ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(27E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(27F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(27F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(27F)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), R^(27F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(27F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ or phenyl), or R^(27F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(27F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵, and R²⁶ are as describedherein.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In some embodiments, R¹⁶ is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —COOR^(16A), —CONR^(16B)R^(16C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C),—NO₂, —SR^(1D), —SO_(n1)R^(1B), SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R¹ is —CN. In embodiments, R¹ is —CN and R²is an unsubstituted C₁-C₃ alkyl. In embodiments, R¹ is —CN and R² ismethyl.

In some embodiments, R¹ is hydrogen, —CN, —CHO, —OR^(1A),—NR^(1B)R^(1C), —C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D),—S(O)_(n1)R^(1B), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), or substituted or unsubstitutedalkyl. In embodiments, R¹ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(1B), or substituted or unsubstituted alkyl. Inembodiments, R¹ is —C(O)OR^(1A) wherein R^(1A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R¹ is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In some embodiments, R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C),—NO₂, SR^(2D), SO_(n2)R^(2B), SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R² is —CN. In embodiments, R² is anunsubstituted C₁-C₃ alkyl.

In some embodiments, R² is hydrogen, —CN, —CHO, —OR^(2A),—NR^(2B)R^(2C), —C(O)OR^(2A), —C(O)NR^(2B)R^(2C), —NO₂, —SR^(2D),—S(O)_(v1)NR^(2B)SO_(v1)NR^(2B)R^(2C), R^(2B)R^(2C), ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), or substituted or unsubstituted alkyl. Inembodiments, R² is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(2B), or substituted or unsubstituted alkyl. Inembodiments, R² is —C(O)OR^(2A) wherein R^(2A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R² is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In some embodiments, R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), CONR^(3B)R^(3C),—NO₂, —SR^(3D), —SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C),—NO₂, —SR^(4D), —SO_(n4)R^(4B), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),ONR^(4B)R^(4C), NHC(O)NHNR^(4B)R^(4C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, R^(1A), R^(1B), R^(1C), R^(2A), R^(2B), R^(2C),R^(2D), R^(3A), R^(3B), R^(3C), R^(3D)R^(4A), R^(4B), R^(4C), R^(4D),R^(16A), R^(16B) and R^(16C) are independently hydrogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R^(16B) and R^(16C), R^(2B) and R^(2C), and R^(1B) andR^(1C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. The symbols n1, n2, n3, and n4are independently an integer from 1 to 4. The symbols, v1, v2, v3, andv4 are independently 1 or 2.

In some embodiments, L¹ is a bond, —O—, —NH—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene. Insome embodiments, L² is a bond, —O—, —NH—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene.

In some embodiments, L¹ is —O—. In some embodiments, L¹ is —NH—. In someembodiments, L¹ is a bond. In some embodiments, L² is —O—. In someembodiments, L² is —NH—. In some embodiments, L² is a bond.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹⁶, R²⁵, R²⁶ and X⁴ are asdescribed herein.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R⁷ is hydrogen. In embodiments, R⁹ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹⁶, R²⁵, R²⁶ and X⁴ are asdescribed herein.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R²⁵, R²⁶, R³² and R³³ and X⁴ are asdescribed herein. In embodiments, R⁵ is hydrogen. In embodiments, R⁶ ishydrogen. In embodiments, R⁷ is hydrogen. In embodiments, R⁹ ishydrogen. In embodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ ishydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the

R¹, R², R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵, R²⁶, X¹ and X² are asdescribed herein. In embodiments, R⁵ is hydrogen. In embodiments, R⁶ ishydrogen. In embodiments, R⁷ is hydrogen. In embodiments, R¹⁰ ishydrogen. In embodiments, R¹¹ is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵ and R²⁶ are as describedherein. In embodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ ishydrogen.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R⁷ is hydrogen. In embodiments, R⁹ is hydrogen. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵, R²⁶, X¹ and X² are asdescribed herein.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R⁵, R⁶, R⁹, R¹⁰, R¹¹, R¹², R¹³, R²⁵, R²⁶, X¹ and X² are asdescribed herein.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R⁹ is hydrogen. In embodiments, R¹⁰ is hydrogen. Inembodiments, R¹¹ is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the

R¹, R², R⁵, R⁶, R⁹, R¹⁰, R¹¹, R¹², R¹³, R²⁵, and R²⁶ are as describedherein.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R⁹ is hydrogen. In embodiments, R¹⁰ is hydrogen. Inembodiments, R¹¹ is hydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

R¹, R², R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R²⁵, R²⁶, X¹ and X²are as described herein are as described herein. In embodiments, R ishydrogen. In embodiments, R⁶ is hydrogen. In embodiments, R⁷ ishydrogen. In embodiments, R¹⁰ is hydrogen. In embodiments, R¹¹ ishydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

wherein R¹, R², R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R²⁵, R²⁶, X¹and X² are as described herein.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

X⁶, X⁷, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁹, R²⁰, R²⁵, and R²⁶ are as describedherein.

In embodiments, X⁶ is —N═. In embodiments, X⁶ is —CR^(23A)═. Inembodiments, X⁷ is —CR^(24A)R^(24B)—. In embodiments, X⁷ is —S—. Inembodiments, X⁷ is —O—. In embodiments, X⁷ is —NR^(24C)—. Inembodiments, X⁶ is —CH═. In embodiments, X⁷ is —CHR^(24B)—. Inembodiments, X⁷ is —CH₂—. In embodiments, X⁷ is —NH—. R^(23A), R^(24A),R^(24B), and R^(24C) are as described herein.

In embodiments, R⁵ is hydrogen. In embodiments, R⁶ is hydrogen. Inembodiments, R¹⁹ is hydrogen. In embodiments, R²⁰ is hydrogen. Inembodiments, R^(23A) is hydrogen. In embodiments, R^(24A) is hydrogen.In embodiments, R^(24B) is hydrogen. In embodiments, R^(24C) ishydrogen.

In embodiments, the compound or the pharmaceutically acceptable saltthereof has the formula:

In embodiments, R¹ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹ is substitutedalkyl (e.g., Ci-C alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R¹ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R¹ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R¹ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R¹ is unsubstituted C₁-C₆ alkyl. In embodiments, R¹ isunsubstituted C₁-C₄ alkyl. In embodiments, R¹ is —CN or —CH₃. Inembodiments, R¹ is —CN. In embodiments, R¹ is —CH₃.

In some embodiments, R¹ is hydrogen, —CN, —CHO, —OR^(1A),—NR^(1B)R^(1C), —C(O)OR^(1A), —C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D),—S(O)_(n1)R^(1B), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), or substituted or unsubstitutedalkyl. In embodiments, R¹ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(1B), or substituted or unsubstituted alkyl. Inembodiments, R¹ is —C(O)OR^(1A) wherein R^(1A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R² is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R² is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R² is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R² is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R² is unsubstituted C₁-C₆ alkyl. In embodiments, R² isunsubstituted C₁-C₄ alkyl. In embodiments, R² is —CN or —CH₃. Inembodiments, R² is —CN. In embodiments, R² is —CH₃.

In some embodiments, R² is hydrogen, —CN, —CHO, —OR^(2A),—NR^(2B)R^(2C), —C(O)OR^(2A), —C(O)NR^(2B)R^(2C), —NO₂, —SR^(2D),—S(O)_(n2)R^(2B), —SO_(v2)NR^(2B)R^(2C), —N—R^(2B)R^(2C),ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), or substituted or unsubstitutedalkyl. In embodiments, R² is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(2B), or substituted or unsubstituted alkyl. Inembodiments, R² is —C(O)OR^(2A) wherein R^(2A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R² is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R³ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³ is substitutedalkyl (e.g., C₁—C alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R³ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R³ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R³ is unsubstituted C₁-C₆ alkyl. In embodiments, R³ isunsubstituted C₁-C₄ alkyl. In embodiments, R³ is —CN or —CH₃. Inembodiments, R³ is —CN. In embodiments, R³ is —CH₃.

In some embodiments, R³ is hydrogen, —CN, —CHO, —OR^(3A),—NR^(3B)R^(3C), —C(O)OR^(3A), —C(O)NR^(3B)R^(3C), —NO₂, —SR^(3D),—S(O)_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), NHNR^(3B)R^(3C),ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), or substituted or unsubstitutedalkyl. In embodiments, R³ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(3B), or substituted or unsubstituted alkyl. Inembodiments, R³ is —C(O)OR^(3A) wherein R^(3A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R³ is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁴ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁴ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R⁴ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R⁴ is unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ isunsubstituted C₁-C₄ alkyl. In embodiments, R⁴ is —CN or —CH₃. Inembodiments, R⁴ is —CN. In embodiments, R⁴ is —CH₃.

In some embodiments, R⁴ is hydrogen, —CN, —CHO, —OR^(4A), NR^(4B)R^(4C),—C(O)OR^(4A), —C(O)NR^(4B)R^(4C), —NO₂, —SR^(4D), —S(O)_(n4)R^(4B),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), or substituted or unsubstituted alkyl. Inembodiments, R⁴ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(4B), or substituted or unsubstituted alkyl. Inembodiments, R⁴ is —C(O)OR^(4A) wherein R^(4A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R⁴ is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R⁵ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁵ is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁵ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁵ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R⁵ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R is unsubstituted C₁-C₆ alkyl. In embodiments, R⁵ isunsubstituted C₁-C₄ alkyl. In embodiments, R⁵ is —CH₃.

In some embodiments, R⁵ is an unsubstituted cyclopropyl. In embodiments,R⁵ is an unsubstituted cyclobutyl. In embodiments, R⁵ is anunsubstituted cyclopentyl. In embodiments, R⁵ is an unsubstitutedcyclohexyl. In embodiments, R⁵ is an unsubstituted C₂-C₄ alkylene. Inembodiments, R⁵ is an unsubstituted C₄ alkylene.

In embodiments, R⁶ is substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ is substitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁶ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁶ is substituted or unsubstituted C₁-C₆ alkyl.In embodiments, R⁶ is substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R⁶ is unsubstituted C₁-C₆ alkyl. In embodiments, R⁶ isunsubstituted C₁-C₄ alkyl. In embodiments, R⁶ is —CH₃.

In some embodiments, R⁶ is an unsubstituted cyclopropyl. In embodiments,R⁶ is an unsubstituted cyclobutyl. In embodiments, R⁶ is anunsubstituted cyclopentyl. In embodiments, R⁶ is an unsubstitutedcyclohexyl. In embodiments, R⁶ is an unsubstituted C₂-C₄ alkylene. Inembodiments, R⁶ is an unsubstituted C₄ alkylene.

In some embodiments, R¹⁶ is substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁶ issubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R¹⁶ is unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl). In embodiments, R¹⁶ is substituted or unsubstitutedC₁-C₆ alkyl. In embodiments, R¹⁶ is substituted or unsubstituted C₁-C₄alkyl. In embodiments, R⁶ is unsubstituted C₁-C₆ alkyl. In embodiments,R¹⁶ is unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁶ is —CN or —CH₃. Inembodiments, R¹⁶ is —CN. In embodiments, R¹⁶ is —CH₃.

In embodiments, R¹⁸ is R^(18E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(18E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(18E)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(18E)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(18E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(18E)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In some embodiments, R¹⁸ is Ring A. In embodiments, Ring A is asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, Ring A is R^(18E)-substitutedor unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,Ring A is R^(18E)-substituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, Ring A is an unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, Ring A is substituted or unsubstituted phenyl,substituted or unsubstituted pyridyl, substituted or unsubstitutedpyrazolyl, substituted or unsubstituted imidazolyl, substituted orunsubstituted oxazolyl, substituted or unsubstituted isoxazolyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedfuranyl, substituted or unsubstituted pyrrolyl, or substituted orunsubstituted thienyl. In embodiments, Ring A is substituted orunsubstituted phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, ortriazinyl.

In embodiments, R²⁵ is —C(O)-L¹-R³² or —C(S)-L¹-R³². R²⁶ is —C(O)-L²-R³³or —C(S)-L²-R³³. In embodiments, R²⁵ and R²⁶ are joined together toform:

In embodiments, R²⁵ and R²⁶ are independently, hydrogen, trityl,para-methoxybenzyl, para-methylbenzyl, acetamidomethyl, tert-butyl,tert-butyl thiol, unsubstituted benzyl, unsubstituted methyl,phenylacyl, or unsubstituted benzyloxycarbonyl.

In embodiments, L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to—C(O)— or —C(S)—. L^(1A) is a bond or —(CH₂)_(z1)—. In embodiments, L²is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to —C(O)— or —C(S)—. L^(1B)is a bond, —O—, or —N^(30B)—, L^(2A) is a bond or —(CH₂)_(z2)—. L^(2B)is a bond, —O—, or —NR^(31B). R^(30B) and R^(31B) are independentlyhydrogen or substituted or unsubstituted alkyl. The symbols z1 and z2are independently an integer from 1 to 10. In embodiments, L^(1A) is—CH₂—. In embodiments, L^(2A) is —CH₂—. In embodiments, L^(1A) andL^(2A) are independently —CH₂—. In embodiments, L^(1A) is —CH₂—. Inembodiments, L^(2A) is —CH₂—.

In embodiments, R²⁵ has the formula:

In embodiments,

R²⁵ has the formula:

In embodiments, R²⁵ has the formula:

In embodiments, R²⁵ has the formula:

In embodiments, R²⁶ has the formula:

In embodiments, R²⁶ has the formula:

In embodiments, R²⁶ hasthe formula:

In embodiments, R²⁶ has the formula:

In embodiments, L^(1B) is —NR^(30B)—; L^(2B) is —NR^(31B); and R^(30B)and R^(31B) are independently unsubstituted C₁-C₃ alkyl.

In embodiments, R²⁵ is —C(O)-L¹-R³². In embodiments, R²⁵ is—C(S)-L¹-R³². In embodiments, R²⁶ is —C(O)-L²-R³³. In embodiments, R²⁶is —C(S)-L²-R³³. In embodiments, R²⁵ is —C(O)-L¹-R³² and R²⁶ is—C(O)-L²-R³³. In embodiments, R²⁵ is —C(S)-L¹-R³² and R²⁶ is—C(S)-L²-R³³.

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In

embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁵ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In

embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R²⁶ is

In embodiments, R³² is halogen, substituted or unsubstituted C₁-C₃alkyl, substituted or unsubstituted aryl. In embodiments, R³² issubstituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R³² is halogen. In embodiments, R³² issubstituted or unsubstituted phenyl. In embodiments, R³² isunsubstituted phenyl. In embodiments, R³² is Cl. In embodiments, R³² issubstituted or unsubstituted C₁-C₃ alkyl. In embodiments, R³² isunsubstituted C₁-C₃ alkyl. In embodiments, R³² is substituted C₁-C₃alkyl. In embodiments, R³² is an unsubstituted C₃ alkyl. In embodiments,R³² is —Cl. In embodiments, R³² is —F. In embodiments, R³² is —CH₃. Inembodiments, R³² is hydrogen.

In embodiments, R³² is hydrogen, halogen, R^(32E)-substituted orunsubstituted C₁-C₃ alkyl, or R^(32E)-substituted or unsubstituted aryl.In embodiments, R³² is halogen, R^(32E)-substituted or unsubstitutedC₁-C₃ alkyl, or R^(32E)-substituted or unsubstituted aryl. Inembodiments, R³² is R^(32E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³² isR^(32E)-substituted or unsubstituted phenyl. In embodiments, R³² isR^(32E)-substituted or unsubstituted C₁-C₃ alkyl. In embodiments, R³² isR^(32E)-substituted or unsubstituted C₁-C₃ alkyl, or R^(32E)-substitutedor unsubstituted aryl. In embodiments, R³² is R^(32E)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³² is R^(32E)-substituted or unsubstituted phenyl. Inembodiments, R³² is R^(32E)-substituted or unsubstituted C₁-C₃ alkyl.

R^(32E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(32F)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(32F)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(32F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(32F)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(32F)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(32F)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(32F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, R³³ is hydrogen, halogen, substituted or unsubstitutedC₁-C₃ alkyl, or substituted or unsubstituted aryl. In embodiments, R³³is substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R³³ is halogen. In embodiments, R³³ issubstituted or unsubstituted phenyl. In embodiments, R³³ isunsubstituted phenyl. In embodiments, R³³ is R^(33E)-substituted orunsubstituted C₁-C₃ alkyl. In embodiments, R³³ is unsubstituted C₁-C₃alkyl. In embodiments, R² is an unsubstituted C₃ alkyl. In embodiments,R³³ is —Cl. In embodiments, R³³ is —F. In embodiments, R³³ is —CH₃. Inembodiments, R³³ is hydrogen.

In embodiments, R³³ is hydrogen, halogen, R^(33E)-substituted orunsubstituted C₁-C₃ alkyl, or R^(33E)-substituted or unsubstituted aryl.In embodiments, R³³ is halogen, R^(33E)-substituted or unsubstitutedC₁-C₃ alkyl, or R^(33E)-substituted or unsubstituted aryl. Inembodiments, R³³ is R^(33E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R³³ isR^(33E)-substituted or unsubstituted phenyl. In embodiments, R³³ isR^(33E)-substituted or unsubstituted C₁-C₃ alkyl. In embodiments, R³³ ishalogen, R^(33E)-substituted or unsubstituted C₁-C₃ alkyl, orR^(33E)-substituted or unsubstituted aryl. In embodiments, R³³ isR^(33E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl). In embodiments, R³³ is R^(33E)-substituted or unsubstitutedphenyl. In embodiments, R³³ is R^(33E)-substituted or unsubstitutedC₁-C₃ alkyl.

R^(33E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(33F)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(33F)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4membered), R^(33F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, or C₅-C₆ cycloalkyl), R^(33F)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), R^(33F)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or R^(33F)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

R^(33F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₅, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R²⁵ may be hydrogen, R^(25E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(25E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(2E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀,C₁₀ aryl, or phenyl), or R^(25E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R²⁵ may be R^(25E)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(25E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(25E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(25E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

In embodiments, R²⁵ is R^(25E)-substituted or unsubstituted alkyl,R^(25E)-substituted or unsubstituted heteroalkyl, R^(25E)-substituted orunsubstituted aryl, or R^(25E)-substituted or unsubstituted heteroaryl.

In embodiments, R²⁵ is R^(25E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁵ isR^(25E)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R²⁵ is an unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁵ is R^(25E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁵ is R^(25E)-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁵ is R^(25E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁵ isR^(25E)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁵ is R^(25E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁵ is R^(25E)-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(25E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(25F)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(25F)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(25F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(25F)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(25F)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(25F)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(25F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R²⁶ may be hydrogen, R^(26E)-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(26E)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 memberedheteroalkyl), R^(26E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀,C₁₀ aryl, or phenyl), or R^(26E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 memberedheteroaryl). R²⁶ may be R^(26E)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, or C₁-C₄ alkyl), R^(26E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2to 4 membered heteroalkyl), R^(26E)-substituted or unsubstituted aryl(e.g., C₆-C₁₀, C₁₀ aryl, or phenyl), or R^(26E)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered heteroaryl).

In embodiments, R²⁶ is R^(26E)-substituted or unsubstituted alkyl(e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁶ isR^(26E)-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R²⁶ is an unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).

In embodiments, R²⁶ is R^(26E)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁶ is R^(26E)-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁶ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁶ is R^(26E)-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁶ isR^(26E)-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁶ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁶ is R^(26E)-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁶ is R^(26E)-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁶ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(26E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(26F)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(26F)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(26F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(26F)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(26F)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(26F)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(26F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2A), R^(2B), R^(2C), R^(2D),R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A),R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B),R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C),R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C),R^(11D), R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C),R^(18D), R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C)Cand R^(20D) are independently hydrogen, hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D)R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D),R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), R^(18D),R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C), andR^(20D) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C),R^(4B) and R^(4C), R^(5B) and R^(5C), R^(6B) and R^(6C), R^(7B) andR^(7C), R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) and R^(10C),R^(11B) and R^(11C), R^(16B) and R^(16C), and R^(18B) and R^(18C)substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B)R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(8A)R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(16A), R^(16B)R^(16C),R^(16D), R^(18A), R^(18B), R^(18C), R^(18D), R^(19A), R^(19B), R^(19C),R^(19D), R^(20A), R^(20B), R^(20C), and R^(20D) are independentlyhydrogen.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R²⁵ and R²⁶ are as described herein.

In embodiments, X³ is —CR⁷═. In embodiments, X³ is —N═. X⁴ is —N═ or—CR⁸—. In embodiments, X⁴ is —CR⁸═. In embodiments, X⁴ is —N═. Inembodiments, X⁵ is —CR⁹═. In embodiments, X⁵ is —N═. In embodiments, X³is —CR⁷═ and X⁴ is —N═ and X⁵ is —CR⁹═ and R⁷, R¹⁰ and R¹¹ areindependently hydrogen and R⁹ is —OCH₃. In embodiments, X³ is —CH═ andX⁴ is —N═ and X⁵ is —CH═ and R¹⁰ and R¹¹ are independently hydrogen. Inembodiments, X³ is —CR⁷═ and X⁵ is —CR⁹═. In embodiments, X³ is —CH═ andX⁵ is —CH═.

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

The symbols R²⁷ and z5 are as described herein. z4 may be an integerfrom 0 to 6.In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

The symbols R²⁷ and z5 are as described herein. In embodiments, R⁸ andR⁹ are optionally joined to form a substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl havingstructural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

The symbols R²⁷ z4 and z5 are as described herein. In embodiments, R⁷and R⁸ are optionally joined to form a substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl havingstructural formula:

In embodiments, R⁷ and R⁸ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, R⁸ and R⁹ are optionally joined to form a substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

In embodiments, L¹ is a bond, —O—, —NH—, R³⁰-substituted orunsubstituted alkylene, R³-substituted or unsubstituted heteroalkylene.In embodiments, L² is a bond, —O—, —NH—, R³¹-substituted orunsubstituted alkylene, R³¹-substituted or unsubstituted heteroalkylene.

R³⁰ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(30E)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(30E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(30E)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(30E)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(30E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(30E)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(30B) may be hydrogen, or R^(30E)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R^(30B) may beR^(30E)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). R^(3B) may be R^(30E)-substituted alkyl (e.g.,C₁-C₅ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R^(30B) may be unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(30B) is hydrogen, or R^(30E)-substituted or unsubstituted C₁-C₄alkyl. In embodiments, R^(30B) is hydrogen, or R^(30E)-substituted orunsubstituted C₁-C₃ alkyl. In embodiments, R^(30B) is hydrogen. Inembodiments, R^(30B) is R^(30E)-substituted C₁-C₃ alkyl. In embodiments,R^(30B) is unsubstituted C₁-C₃ alkyl. In embodiments, R^(30B) ishydrogen. In embodiments, R^(30B) is —CH₃.

R^(30E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(30F)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(30F)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(30F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(30F)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(30F)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(30F)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(30F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

R³¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(31E)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(31E)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(31E)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(31E)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(31E)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(3E)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(31B) may be hydrogen, or R^(31E)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R^(31B) may beR^(31E)-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). R^(31B) may be R^(31E)-substituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). R^(31B) may be unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(31B) is hydrogen, or R^(31E)-substituted or unsubstituted C₁-C₄alkyl. In embodiments, R^(31B) is hydrogen, or R^(3E)-substituted orunsubstituted C₁-C₃ alkyl. In embodiments, R^(31B) is hydrogen. Inembodiments, R^(31B) is R^(31E)-substituted C₁-C₃ alkyl. In embodiments,R^(31B) is unsubstituted C₁-C₃ alkyl. In embodiments, R^(31B) ishydrogen. In embodiments, R^(31B) is —CH₃.

R^(31E) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCl₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, R^(31F)-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(31F)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl),R^(31F)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R^(31F)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(31F)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl), or R^(31F)-substituted or unsubstituted heteroaryl (e.g., 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R^(31F) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —C₃, —CHF₂,—CHCl₂, —CHBr₂, —CHI₂, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —N₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHl₂, —OCH₂F, —OCH₂Cl,—OCH₂Br, —OCH₂I, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀aryl or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered heteroaryl).

In embodiments, the compound or pharmaceutically acceptable salt has theformula having the formula:

wherein X³, X⁴, X⁵, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵ and R²⁶are as described herein.

R¹⁶ is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(16A), —CONR^(16B)R^(16C), substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂, —SR^(1D),—SO_(n1)R^(1B), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹is —CN. In embodiments, R¹ is —CN and R^(1.2) is an unsubstituted C₁-C₃alkyl. In embodiments, R¹ is —CN and R^(1.2) is methyl. In embodiments,R¹ is hydrogen, —CN, —CHO, OR^(1A), NR^(1B)R^(1C), —C(O)OR^(1A),C(O)NR^(1B)R^(1C), —NO₂, —SR^(1D), —S(O)_(n1)R^(1B),—SO_(v1)NR^(1B)R^(1C), —R^(1B)R^(1C), ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), or substituted or unsubstituted alkyl. Inembodiments, R¹ is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(1B), or substituted or unsubstituted alkyl. Inembodiments, R¹ is —C(O)OR^(1A) wherein R^(1A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R¹ is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R¹ is hydrogen. In embodiments, R¹ is —CH₃. Inembodiments, R¹ is —N(CH₃)₂. In embodiments, R¹ is —CN. In embodiments,R is —CH₂OCH₃. In embodiments, R¹ is —C(O)OCH₃. In embodiments, R¹ is—C(O)OCH₂CH₂CH₂CH₃. In embodiments, R¹ is —C(O)OC(CH₃)₄. In embodiments,R¹ is

R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²is —CN. In embodiments, R² is an unsubstituted C₁-C₃ alkyl. Inembodiments, R² is hydrogen, —CN, —CHO, —OR^(2A), —NR^(2B)R^(2C),—C(O)OR^(2A), C(O)NR^(2B)R^(2C)—NO₂, SR^(2D), S(O)_(n1)R^(2B),—SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), or substituted or unsubstituted alkyl. Inembodiments, R² is hydrogen, —CN, —CHO, —OCH₃, —N(CH₃)₂, —NH₂,—C(O)OCH₃, —S(O)₂R^(2B), or substituted or unsubstituted alkyl. Inembodiments, R² is —C(O)OR^(2A) wherein R^(2A) is substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R² is hydrogen, —CH₃, —N(CH₃)₂, —CN, —CH₂OCH₃, —C(O)OCH₃,—C(O)OCH₂CH₂CH₂CH₃, —C(O)OC(CH₃)₄, or

In embodiments, R² is hydrogen. In embodiments, R² is —CH₃. Inembodiments, R² is —N(CH₃)₂. In embodiments, R² is —CN. In embodiments,R² is —CH₂OCH₃. In embodiments, R² is —C(O)OCH₃. In embodiments, R² is—C(O)OCH₂CH₂CH₂CH₃. In embodiments, R² is —C(O)OC(CH₃)₄. In embodiments,R² is

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, SR^(3D),SO_(n3)R^(3B), SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂, SR^(4D),SO_(n4)R^(4B), SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, the compound has the formula:

wherein R¹², R²⁵, and R²⁶ are as described herein. In embodiments, R²⁵and R²⁶ are independently —C(O)CH₃. In embodiments, R²⁵ and R²⁶ are both—C(O)CH₃. In embodiments, R⁹ is —OCH₃. In embodiments, R²⁵ and R²⁶ areindependently —C(O)CH₃, —C(O)OPh, —C(O)CH₂OCH₃, C(O)NHPh, or —C(S)OPh.

In embodiments, the compound has the formula:

wherein R²⁵ and R²⁶ are as described herein. In embodiments, R²⁵ and R²⁶are independently —C(O)CH₃. In embodiments, R²⁵ and R²⁶ are both—C(O)CH₃. In embodiments, R²⁵ and R²⁶ are independently —C(O)CH₃,—C(O)OPh, —C(O)CH₂OCH₃, C(O)NHPh, or —C(S)OPh.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁸, R²⁵ and R²⁶ are as describedherein, or a pharmaceutically acceptable salt thereof.

In embodiments, R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂,—SR^(1D), —SO_(n1)R^(1B), SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂,—SR^(2D), SO_(n2)R^(2B), SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(1A), —CONR^(3B)R^(3C), —NO₂,—SR^(3D), —SO_(n3)R^(3B), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂,—SR^(4D), —SO_(n4)R^(4B), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R¹⁶ is hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —COOR^(6A), —CONR^(16B)R^(16C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(16A),R^(16B), and R^(16C) are independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(16B) and R^(16C), R^(2B) and R^(2C), R^(1B) and R^(1C), R^(3B) andR^(3C), and R^(4B) and R^(4C) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

In embodiments, R⁵ is hydrogen, halogen, —N₅, —CF₅, —CCl₅, —CBr₅, —CI₅,—CN, —CHO, —OR^(5A), NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C), —NO₂,—SR^(5D), —SO_(n5)R^(5B), SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R⁶ is hydrogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—COOR^(6A), —CONR^(6B)R^(6C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R²⁵ is —C(O)-L¹-R³² or —C(S)-L-R³². In embodiments, R²⁶is —C(O)-L²-R³ or —C(S)-L²-R³³. In embodiments, R²⁵ and R²⁶ mayoptionally be joined to form

In embodiments, L is a bond, —O—, —NH—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene. In embodiments,L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene. In embodiments, R³² and R³³are independently hydrogen, halogen, substituted or unsubstituted C₁-C₃alkyl, substituted or unsubstituted aryl. In embodiments, R³² and R³³are independently halogen, substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted aryl. In embodiments, R¹⁸ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(18A),—NR^(18B)R^(18C), —C(O)OR^(19A), C(O)NR^(18B)R^(18C), —NO₂, —SR^(18D),—S(O)_(n18)R^(18B), —SO_(v1)NR^(18B)R^(18C), —NHNR^(18B)R^(18C),ONR^(18B)R^(18C), —NHC(O)NHNR^(18B)R^(18C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C),R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(16A),R^(16B), R^(16C), R^(18A), R^(18B), R^(18C), and R^(18D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and R^(1B) and R^(1C), R^(2B)and R^(2C), R^(3B) and R^(3C), R^(4B) and R^(4C), R^(5B) and R^(5C),R^(6B) and R^(6C), R^(7B) and R^(7C), R^(8B) and R^(8C), R^(9B) andR^(9C), R^(10B) and R^(10C), R^(11B) and R^(11C), R^(16B) and R^(16C),and R^(18B) and R^(18C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. Inembodiments, n1, n2, n3, n4, n5, n16, and n18 are independently aninteger from 1 to 4; and v1, v2, v3, v4, n5, v16, and v18, andindependently 1 or 2.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein X³, X⁴, X⁵, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵ and R²⁶are as described herein, or a pharmaceutically acceptable salt thereof.

In embodiments, X³ is —N═ or —CR⁷═. In embodiments, X⁴ is —N═ or —CR⁸═.In embodiments, X⁵ is —N═ or —CR⁹═. In embodiments, R⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(7A),—NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C), —NR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂,—SR^(8D), SO_(n8)R^(8B), SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R⁷ and R⁸ may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl.

In embodiments, R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂,—SR^(9D)D, SO_(n9)R^(9B), SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁸ and R⁹ may optionally be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.

In embodiments, R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C),—NO₂, —SR^(10D), —SO_(n10)R^(10B), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(11A), NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C),—NO₂, —SR^(11D), —SO_(n11)R^(11B), —SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B),R^(8C)R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C), and R^(11D) are independentlyhydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R^(7B) and R^(7C), R^(8B) andR^(8C), and R^(9B) and R^(9C), R^(10B) and R^(10C), and R^(11B) andR^(11C), substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. In embodiments, n7, n8, n9,n10, and n11 are independently an integer from 1 to 4. In embodiments,v7, v8, v9, v10 and v11 are independently 1 or 2.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein X⁴, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹⁶, R²⁵ and R²⁶are as described herein.

In some embodiments, R⁷ and R⁸ or R⁸ and R⁹ are optionally joined toform a substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl having structural formula:

In some embodiments, R⁷ and R⁸ or R⁸ and R⁹ are optionally joined toforma substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl having structural formula:

In embodiments, X¹ is —O—, —NR^(21C)—, or —S—. In embodiments, X² is—O—, —NR^(22C)—, or —S—. In embodiments, z5 is an integer from 0 to 8.In embodiments, m is 1 or 2.

In embodiments, R¹² and R¹³ are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein X¹, X², R¹, R², R, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵ and R²⁶ areas described herein.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments the compound or pharmaceutically acceptable salt thereof,has the formula:

wherein X¹, X², R¹, R², R⁵, R⁶, R⁹, R¹⁰, R¹¹, R¹², R¹³, R²⁵ and R²⁶ areas described herein.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein X¹, X², R¹, R², R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵ and R²⁶ areas described herein.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

wherein X⁶, X⁷, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁹, R²⁰, R²⁵ and R²⁶ areas described herein.

In embodiments, the compound or pharmaceutically acceptable saltthereof, has the formula:

In some embodiments, R¹⁰ and R¹¹ are independently hydrogen. In someembodiments, X⁴ is —N═. In some embodiments, R⁹ is —OCH₃. In someembodiments, R² is substituted or unsubstituted alkyl.

In some embodiments, R² is substituted or unsubstituted C₁-C₃ alkyl. Insome embodiments, R² is methyl. In some embodiments, R¹ is —CN. In someembodiments, R²⁵ is —C(O)-L¹-R³² or —C(S)-L¹-R³²; and R²⁶ is—C(O)-L²-R³³ or —C(S)-L²-R³³.

In some embodiments, R²⁵ is —C(O)-L¹-R³²; and R²⁶ is —C(O)-L²-R³³.

In some embodiments, R²⁵ is —C(S)-L¹-R³²; and R²⁶ is —C(S)-L²-R³³.

In some embodiments, L¹ and L² are independently —O—.

In some embodiments, L¹ and L² are independently-NH—.

In some embodiments, L¹ and L² are independently a bond.

In some embodiments, L¹ is -L^(1A)-L^(1B), wherein L^(1A) is bonded to—C(O)— or —C(S)—; and L² is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to—C(O)— or —C(S)—; L^(1A) is a bond or —(CH₂)_(z1)—; L^(1B) is a bond,—O— or —NR^(30B)—. L^(2A) is a bond or —(CH₂)_(z2)—; L^(2B) is a bond,—O— or —NR^(31B)—; z1 and z2 are independently an integer from 1 to 10;and R³⁰ and R³¹ are independently hydrogen or substituted orunsubstituted alkyl.

In some embodiments, L^(1A) and L^(2A) are independently —CH₂—.

In some embodiments, L^(1B) is —NR^(30B)—, L^(2B) is —NR^(31B)—; andR^(30B) and R^(31B) are independently unsubstituted C₁-C₃ alkyl.

In some embodiments, R³² and R³³ are independently unsubstituted C₁-C₃alkyl or unsubstituted aryl.

In some embodiments, R³² and R³³ are independently unsubstituted aryl.

In some embodiments, R³² and R³³ are independently halogen. In someembodiments, R³² and R³³ are independently hydrogen.

In some embodiments, R²⁵ and R²⁶ are joined together to form:

In some embodiments, R⁶ is methyl.

In some embodiments, the compound or pharmaceutically acceptable saltthereof, has the structure:

In embodiments, the compound has the structure

In embodiments, the compound has the structure:

In embodiments, the compound has the structure:

Further Forms of Compounds

Isomers

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or a combinationthereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

Tautomers

In some situations, compounds may exist as tautomers. All tautomers areincluded within the formula described herein.

Labelled Compounds

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels, orphotoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ^(3D)I,respectively. Certain isotopically-labeled compounds described herein,for example those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements.

Salts

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, ortris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

Solvates

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and may be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds describedherein can be conveniently prepared or formed during the processesdescribed herein. In addition, the compounds provided herein can existin unsolvated as well as solvated forms. In general, the solvated formsare considered equivalent to the unsolvated forms for the purposes ofthe compounds and methods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein isaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in FIESER ANDFIESER'S REAGENTS FOR ORGANIC SYNTHESIS, Volumes 1-17 (John Wiley andSons, 1991); RODD'S CHEMISTRY OF CARBON COMPOUNDS, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989); March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001); and Green andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compounds as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guide,the following synthetic methods may be utilized as described inInternational Patent Application PCT/US2013/066252, which is hereinincorporated by reference for this disclosure.

In certain embodiments, the compound is a compound as set forth in Table1.

TABLE 1 Exemplary embodiments of compounds provided herein. StructureReference

ETP6

ETP8

ETP12

ETP14

ETP27

ETP49

ETP56

ETP69

ETP95

ETP100

ETP120

ETP125

ETP128

ETP130

ETP154

ETP167

ETP178

ETP195

ETP204

ETP206

ETP214

ETP218

ETP223

ETP229

ETP303

ETP309

ETP313

ETP328

ETP331

ETP341

ETP344

ETP356

ETP359

ETP365

ETP382

ETP384

ETP390

ETP406

ETP417

ETP422

ETP425

ETP442

ETP450

ETP452

ETP469

ETP484

ETP493

Pharmaceutical Composition

Described herein are pharmaceutical compositions comprising a compound(ETP compound) provided herein, including a bridged ETP compound (e.g.formula (1), (I), (I(S)), (I(R)), (II), (II(S)), (II(R)), (II1),(II1(S)), (II1(R)), (II2), (II2(S)), (II2(R)), (II3), (II3(S)),(II3(R)), (II4), (II5), (III), (III(S)), (III(R)), (III1), (III1(S)),(III1(R)), (IV), (IV(S)), (IV(R)), (IV1), (IV1(S)), (IV1(R)), (IV2),(IV2(S)), (IV2(R)), (V), (V(S)), (V(R)), (V1), (V1(S)), (V1(R)), (V2),(V2(S)), (V2(R)), (V3), (V3(S)), (V3(R)), (V4), (V4(S)), (V4(R)), (VI),(VI(S)), (VI(R)), (VII), (VI1(S)), (VI1(R))), (XXI), (XXIa), (XXII),(XXII(S)), (XXII(R)), (XXIII), (XXIII(S)), (XXIII(R)), (XXIV),(XXIV(S)), (XXIV(R)), (XXV), (XXV(S)), (XXV(R)), (XXVI), (XXVI(S)),(XXVI(R)), (XXVII), (XXVII(S)), (XXVII (R)), (XXVIII), (XXVII(S)),(XXVIII(R)), (XXIX), (XXIX (S)), (XXIX (R)), (XXX), (XXXI), (XXI′),(XXII′), (XXIII′), (XXIII′(S)), (XXIII′(R)), (XXIV′), (XXIV′(S)),(XXIV′(R)), (XXV′), (XXV′(S)), (XXV′(R)), (XXVI′), (XXVI′(S)), and(XXVI′(R)), described herein. In some embodiments, the pharmaceuticalcomposition refers to a mixture of a bridged ETP compound describedherein with an excipient. In some embodiments, the excipient is acarrier, binder, filling agent, suspending agent, flavoring agent,sweetening agent, disintegrating agent, dispersing agent, surfactant,lubricant, colorant, diluent, solubilizer, moistening agent,plasticizer, stabilizer, penetration enhancer, wetting agent,antifoaming agent, antioxidant, preservative, or one or more combinationthereof. The pharmaceutical composition facilitates administration ofthe ETP compound described herein to an organism. In practicing themethods of treatment or use provided herein, therapeutically effectiveamounts of the ETP compound described herein are administered in apharmaceutical composition to a mammal having a disease, disorder, orcondition to be treated. In some embodiments, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The ETP compounddescribed herein can be used singly or in combination with one or moretherapeutic agents as components of mixtures (as in combinationtherapy).

The pharmaceutical compositions described herein are administered to asubject by multiple administration routes, including, but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, inhalation, buccal, topical, rectal, or transdermaladministration routes. In some embodiments, pharmaceutical compositionsdescribed herein, which include a bridged ETP compound described herein,are formulated into any suitable dosage form, including, but not limitedto, emulsions suitable for injection, nanosuspensions suitable forinjection, aqueous oral dispersions, liquids, gels, syrups, elixirs,slurries, suspensions, aerosols, controlled release formulations, fastmelt formulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulates formulations, and mixed immediaterelease and controlled release formulations.

Described herein are pharmaceutical compositions comprising a compound(ETP compound) provided herein, including a bridged ETP compound (e.g.formula (1), (I), (I(S)), (I(R)), (II), (II(S)), (II(R)), (II1),(II(S)), (II1(R)), (II2), (II2(S)), (II2(R)), (II3), (II3(S)), (II3(R)),(II4), (II5), (III), (III(S)), (III(R)), (III1), (III1(S)), (III1(R)),(IV), (IV(S)), (IV(R)), (IV1), (IV(S)), (IV1(R)), (IV2), (V2(S)),(V2(R)), (V), (V(S)), (V(R)), (VI), (VI(S)), (V1(R)), (V2), (V2(S)),(V2(R)), (V3), (V3(S)), (V3(R)), (V4), (V4(S)), (V4(R)), (VI), (VI(S)),(VI(R)), (VI1), (VI1(S)), (VI1(R))), (XXI), (XXIa), (XXII), (XXII(S)),(XXII(R)), (XXIII), (XXIII(S)), (XXIII(R)), (XXIV), (XXIV(S)),(XXIV(R)), (XXV), (XXV(S)), (XXV(R)), (XXVI), (XXVI(S)), (XXVI(R)),(XXVII), (XXVII(S)), (XXVII (R)), (XXVIII), (XXVIII(S)), (XXVIII(R)),(XXIX), (XXIX (S)), (XXIX (R)), (XXX), (XXXI), (XXI′), (XXII′),(XXIII′), (XXIII′(S)), (XXIII′(R)), (XXIV′), (XXIV′(S)), (XXIV′(R)),(XXV′), (XXV′(S)), (XXV′(R)), (XXVI′), (XXVI′(S)), and (XXVI′(R)),described herein formulated for oral administration. In someembodiments, the pharmaceutical composition for oral use is a tablet,(including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In some embodiments, thepharmaceutical composition for oral use is a solid dosage form, e.g.,tablets, effervescent tablets, and capsules. In some embodiments, thesolid dosage form are prepared by mixing particles of a bridged ETPcompound described herein, with one or more pharmaceutical excipients toform a bulk blend composition. When referring to these bulk blendcompositions as homogeneous, it is meant that the particles of the ETPcompound described herein, are dispersed evenly throughout thecomposition so that the composition may be subdivided into equallyeffective unit dosage forms, such as tablets, pills, and capsules. Theindividual unit dosages may also include film coatings, whichdisintegrate upon oral ingestion or upon contact with diluent.

The compositions disclosed herein can be delivered transdermally, by atopical route, formulated as applicator sticks, solutions, suspensions,emulsions, gels, creams, ointments, pastes, jellies, paints, powders,and aerosols. Oral preparations include tablets, pills, powder, dragees,capsules, liquids, lozenges, cachets, gels, syrups, slurries,suspensions, etc., suitable for ingestion by the patient. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. Liquid form preparationsinclude solutions, suspensions, and emulsions, for example, water orwater/propylene glycol solutions. The compositions of the presentdisclosure may additionally include components to provide sustainedrelease and/or comfort.

Pharmaceutical compositions may include compositions wherein the activeingredient (e.g. compounds described herein, including embodiments orexamples) is contained in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application may depend, inter alia, on thecondition being treated. When administered in methods to treat adisease, such compositions may contain an amount of active ingredienteffective to achieve the desired result, e.g., modulating the activityof a target molecule, and/or reducing, eliminating, or slowing theprogression of disease symptoms.

Generally, the ETP compound described herein is administered in anamount effective for amelioration of the symptoms of the disease ordisorder (i.e., a therapeutically effective amount). In someembodiments, the therapeutically effective amount is an amount that iscapable of at least partially preventing or reversing a disease ordisorder. In some embodiments, the dose required to obtain an effectiveamount varies depending on the agent, formulation, disease or disorder,and individual to whom the ETP compound described herein isadministered.

In some embodiments, the determination of the effective amount involvesin vitro assays in which varying doses of the ETP compound describedherein are administered to cells in culture and the concentration ofagent effective for ameliorating some or all symptoms is determined inorder to calculate the concentration required in vivo. In someembodiments, the effective amounts are based on in vivo animal studies.

In some embodiments, the ETP compound described herein is administeredprior to, concurrently with, and subsequent to the appearance ofsymptoms of a disease or disorder. In some embodiments, the ETP compounddescribed herein is administered to a subject with a family history ofthe disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

Methods

Described herein are methods for treating T-cell lymphoma in a subjectin need thereof, comprising administering to the subject in needthereof, a therapeutically effective amount of a compound (ETP compound)provided herein, including compounds having the structure of formula(e.g. formula (1), (I), (I(S)), (I(R)), (II), (II(S)), (II(R)), (II1),(II1(S)), (II1(R)), (II2), (II2(S)), (II2(R)), (II3), (II3(S)),(II3(R)), (II4), (II5), (III), (III(S)), (III(R)), (III1), (III1(S)),(III1(R)), (IV), (IV(S)), (IV(R)), (IV1), (IV1(S)), (IV1(R)), (IV2),(IV2(S)), (IV2(R)), (V), (V(S)), (V(R)), (V1), (V1(S)), (V1(R)), (V2),(V2(S)), (V2(R)), (V3), (V3(S)), (V3(R)), (V4), (V4(S)), (V4(R)), (VI),(VI(S)), (VI(R)), (VI1), (VI1(S)), (VII(R))), (XXI), (XXIa), (XXII),(XXII(S)), (XXII(R)), (XXIII), (XXIII(S)), (XXIII(R)), (XXIV),(XXIV(S)), (XXIV(R)), (XXV), (XXV(S)), (XXV(R)), (XXVI), (XXVI(S)),(XXVI(R)), (XXVII), (XXVII(S)), (XXVII (R)), (XXVIII), (XXVIII(S)),(XXVIII(R)), (XXIX), (XXIX (S)), (XXIX (R)), (XXX), (XXXI), (XXI′),(XXII′), (XXIII′), (XXIII′(S)), (XXIII′(R)), (XXIV′), (XXIV′(S)),(XXIV′(R)), (XXV′), (XXV′(S)), (XXV′(R)), (XXVI′), (XXVI′(S)), and(XXVI′(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (1), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (I), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (I(S)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (I(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (II), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (II(S)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (II(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (III), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (III(S)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (III(R)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (IV), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (IV(S)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (IV(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (V), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (V(S)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (V(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (VI), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (VI(S)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (VI(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXI), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXIa), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXII), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXII(S)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXII(R)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXIII), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXIII(S)), including embodiments thereof. In some embodimentsof a method of treating T-cell lymphoma, the compound has the structureof formula (XXIII(R)), including embodiments thereof. In someembodiments of a method of treating T-cell lymphoma, the compound hasthe structure of formula (XXIV), including embodiments thereof. In someembodiments of a method of treating T-cell lymphoma, the compound hasthe structure of formula (XXIV(S)), including embodiments thereof. Insome embodiments of a method of treating T-cell lymphoma, the compoundhas the structure of formula (XXIV(R)), including embodiments thereof.In some embodiments of a method of treating T-cell lymphoma, thecompound has the structure of formula (XXV), including embodimentsthereof. In some embodiments of a method of treating T-cell lymphoma,the compound has the structure of formula (XXV(S)), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXV(R)), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXVI(S)), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXVI(R)), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXVII), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXVII(S)),including embodiments thereof. In some embodiments of a method oftreating T-cell lymphoma, the compound has the structure of formula(XXVII (R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXVIII), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXVIII(S)), including embodiments thereof. In some embodimentsof a method of treating T-cell lymphoma, the compound has the structureof formula (XXVIII(R)), including embodiments thereof. In someembodiments of a method of treating T-cell lymphoma, the compound hasthe structure of formula (XXIX), including embodiments thereof. In someembodiments of a method of treating T-cell lymphoma, the compound hasthe structure of formula (XXIX (S)), including embodiments thereof. Insome embodiments of a method of treating T-cell lymphoma, the compoundhas the structure of formula (XXIX (R)), including embodiments thereof.

In some embodiments of a method of treating T-cell lymphoma, thecompound has the structure of formula (XXX), including embodimentsthereof. In some embodiments of a method of treating T-cell lymphoma,the compound has the structure of formula (XXXI), including embodimentsthereof. In some embodiments of a method of treating T-cell lymphoma,the compound has the structure of formula (XXI′), including embodimentsthereof. In some embodiments of a method of treating T-cell lymphoma,the compound has the structure of formula (XXII′), including embodimentsthereof. In some embodiments of a method of treating T-cell lymphoma,the compound has the structure of formula (XXIII′), includingembodiments thereof. In some embodiments of a method of treating T-celllymphoma, the compound has the structure of formula (XXIII′(S)),including embodiments thereof. In some embodiments of a method oftreating T-cell lymphoma, the compound has the structure of formula(XXIII′(R)), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXIV′), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXIV′(S)), including embodiments thereof. In some embodimentsof a method of treating T-cell lymphoma, the compound has the structureof formula (XXV′), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXV′(S)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXV′(R)), including embodiments thereof. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (XXVI′), including embodiments thereof. In some embodiments of amethod of treating T-cell lymphoma, the compound has the structure offormula (XXVI′(S)), including embodiments thereof. In some embodimentsof a method of treating T-cell lymphoma, the compound has the structureof formula (XXVI′(R)), including embodiments thereof.

Also described herein are methods of treating T-cell lymphoma in asubject in need thereof, comprising administering to the subject in needthereof, a bridged ETP compound described herein. In some embodiments ofa method of treating T-cell lymphoma, the compound has the structure offormula (1), including embodiments thereof. In some embodiments, the ETPcompound is a compound having the structure of formula (I), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (I(S)), or a pharmaceutically acceptablesalt or a pharmaceutically acceptable solvate thereof. In someembodiments, the ETP compound is a compound having the structure offormula (I(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (II), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (II(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (II(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (III), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (III(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (III(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (IV), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (IV(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (IV(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (V), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (V(S)), or a pharmaceutically acceptablesalt or a pharmaceutically acceptable solvate thereof. In someembodiments, the ETP compound is a compound having the structure offormula (V(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (VI), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (VI(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (VI(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXI), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIa), or a pharmaceutically acceptablesalt or a pharmaceutically acceptable solvate thereof. In someembodiments, the ETP compound is a compound having the structure offormula (XXII), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXII(S)), ora pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXII(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXIII), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXIII(S)),or a pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIII(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXIV), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXIV(S)), ora pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIV(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXV), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXV(S)), ora pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXV(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXVI), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXVI(S)), ora pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXVI(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXVII), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXVII(S)),or a pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXVII(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXVIII), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXVIII(S)),or a pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXVIII(R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXIX), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXIX (S)),or a pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIX (R)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXX), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXXI), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXI′), or a pharmaceutically acceptablesalt or a pharmaceutically acceptable solvate thereof. In someembodiments, the ETP compound is a compound having the structure offormula (XXII′), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXIII′), ora pharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIII′(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXIII′(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXIV′), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXIV′(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXIV′(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXV′), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXV′(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXV′(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof. In some embodiments, theETP compound is a compound having the structure of formula (XXVI′), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof. In some embodiments, the ETP compound is a compoundhaving the structure of formula (XXVI′(S)), or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof. Insome embodiments, the ETP compound is a compound having the structure offormula (XXVI′(R)), or a pharmaceutically acceptable salt or apharmaceutically acceptable solvate thereof.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is cutaneous T-cell lymphoma. In some embodiments of a methodof treating T-cell lymphoma, the cutaneous T-cell lymphoma is Sezarysyndrome. In some embodiments of a method of treating T-cell lymphoma,the cutaneous T-cell lymphoma is mycosis fungoides. In some embodimentsof a method of treating T-cell lymphoma, the cutaneous T-cell lymphomais folliculotropic mycosis fungoides. In some embodiments of a method oftreating T-cell lymphoma, the cutaneous T-cell lymphoma is pagetoidreticulosis. In some embodiments of a method of treating T-celllymphoma, the cutaneous T-cell lymphoma is granulomatous slack skin. Insome embodiments of a method of treating T-cell lymphoma, the cutaneousT-cell lymphoma is primary cutaneous CD30+ T-cell lymphoproliferativedisorder. In some embodiments of a method of treating T-cell lymphoma,the cutaneous T-cell lymphoma is lymphomatoid papulosis. In someembodiments of a method of treating T-cell lymphoma, the cutaneousT-cell lymphoma is primary cutaneous anaplastic large-cell lymphoma. Insome embodiments of a method of treating T-cell lymphoma, the cutaneousT-cell lymphoma is primary cutaneous γδ T-cell lymphoma. In someembodiments of a method of treating T-cell lymphoma, the cutaneousT-cell lymphoma is primary cutaneous CD8+ aggressive epidermotropiclymphoma. In some embodiments of a method of treating T-cell lymphoma,the cutaneous T-cell lymphoma is primary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphoma. In some embodiments of amethod of treating T-cell lymphoma, the cutaneous T-cell lymphoma isprimary cutaneous CD4+ small/medium T-cell lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is nodal T-cell lymphoma. In some embodiments of a method oftreating T-cell lymphoma, the nodal T-cell lymphoma is follicular T-celllymphoma. In some embodiments of a method of treating T-cell lymphoma,the nodal T-cell lymphoma is angioimmunoblastic T-cell lymphoma. In someembodiments of a method of treating T-cell lymphoma, the nodal T-celllymphoma is nodal peripheral T-cell lymphoma with TFH phenotype. In someembodiments of a method of treating T-cell lymphoma, the nodal T-celllymphoma is anaplastic large cell lymphoma ALK+. In some embodiments ofa method of treating T-cell lymphoma, the nodal T-cell lymphoma isanaplastic large cell lymphoma ALK−. In some embodiments of a method oftreating T-cell lymphoma, the nodal T-cell lymphoma is breastimplant-associated anaplastic large-cell lymphoma. In some embodimentsof a method of treating T-cell lymphoma, the nodal T-cell lymphoma isperipheral T-cell lymphoma not otherwise specified (PTCL-NOS).

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is extranodal T-cell lymphoma. In some embodiments of a methodof treating T-cell lymphoma, the extranodal T-cell lymphoma is systemicEBV+ T-cell lymphoma of childhood. In some embodiments of a method oftreating T-cell lymphoma, the extranodal T-cell lymphoma is hydroavacciniforme-like lymphoproliferative disorder. In some embodiments of amethod of treating T-cell lymphoma, the extranodal T-cell lymphoma isextranodal NK/T-cell lymphoma nasal type. In some embodiments of amethod of treating T-cell lymphoma, the extranodal T-cell lymphoma isenteropathy-associated T-cell lymphoma. In some embodiments of a methodof treating T-cell lymphoma, the extranodal T-cell lymphoma ishepatosplenic T-cell lymphoma. In some embodiments of a method oftreating T-cell lymphoma, the extranodal T-cell lymphoma is subcutaneouspanniculitis-like T-cell lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is leukemic T-cell lymphoma. In some embodiments of a method oftreating T-cell lymphoma, the leukemic T-cell lymphoma is T-cellprolymphocytic leukemia. In some embodiments of a method of treatingT-cell lymphoma, the leukemic T-cell lymphoma is T-cell large-granularlymphocytic leukemia. In some embodiments of a method of treating T-celllymphoma, the leukemic T-cell lymphoma is adult T-cellleukemia/lymphoma.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is monomorphic epitheliotropic intestinal T-cell lymphoma. Insome embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is indolent T-cell lymphoproliferative disorder of thegastrointestinal tract.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is peripheral T-cell lymphoma, anaplastic large-cell lymphoma,angioimmunoblastic T-cell lymphoma, adult T-cell Leukemia/Lymphoma,blastic natural killer (NK) cell lymphoma, enteropathy-associated T-celllymphoma, hepatosplenic T-cell lymphoma, lymphoblastic lymphoma, ornasal natural killer (NK)/T-cell lymphoma.

Also described herein are methods for treating T-cell lymphoma in asubject in need thereof, comprising administering to the subject in needthereof, a bridged ETP compound described herein, thereby reducing,ameliorating or eliminating a symptom or manifestation of T-celllymphoma. In some embodiments of a method of treating T-cell lymphoma,the subject in need thereof is predisposed to T-cell lymphoma, but doesnot yet manifest a symptom of T-cell lymphoma. In some embodiments of amethod of treating T-cell lymphoma, the administration of a bridged ETPcompound described herein effectively prevents or delays development ofsymptoms associated with T-cell lymphoma. In some embodiments of amethod of treating T-cell lymphoma, the symptoms of T-cell lymphomacomprise at least one of the following symptoms: chest pain, coughing,difficulty breathing, fatigue, loss of appetite, weight loss, alopecia,follicular cysts, comedolike lesions, nail dystrophy, fever, nightsweats, itchy skin, swollen lymph nodes, lymphadenopathy,hepatosplenomegaly, autoimmune phenomena, swollen abdomen, painfulabdomen, edematous skin, atopic dermatitis, nonspecific dermatitis,nonspecific chronic dermatitis, parapsoriasis, patches on lower trunk,patches on buttocks, palmar hyperkeratosis, plantar hyperkeratosis,minimal/absent pruritus, and intensely pruritic plaques.

In some embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is associated with at least one of the following conditions:smoking, obesity, infection, HIV, Epstein-Barr virus, humanT-lymphotropic virus, Helicobacter pyroli infection, chronicHelicobacter pyroli infection, exposure to chemicals, exposure toinsecticides, exposure to pesticides, use of immunosuppressant drugs,weakened immune system, genetic disorders, previous chemotherapy, andprevious radiation therapy. In some embodiments of a method of treatingT-cell lymphoma, the T-cell lymphoma is associated with smoking. In someembodiments of a method of treating T-cell lymphoma, the T-cell lymphomais associated with obesity. In some embodiments of a method of treatingT-cell lymphoma, the T-cell lymphoma is associated with infection. Insome embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is associated with HIV. In some embodiments of a method oftreating T-cell lymphoma, the T-cell lymphoma is associated withEpstein-Barr virus. In some embodiments of a method of treating T-celllymphoma, the T-cell lymphoma is associated with human T-lymphotropicvirus. In some embodiments of a method of treating T-cell lymphoma, theT-cell lymphoma is associated with Helicobacter pyroli infection. Insome embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is associated with chronic Helicobacter pyroli infection. Insome embodiments of a method of treating T-cell lymphoma, the T-celllymphoma is associated with exposure to chemicals. In some embodimentsof a method of treating T-cell lymphoma, the T-cell lymphoma isassociated with exposure to insecticides. In some embodiments of amethod of treating T-cell lymphoma, the T-cell lymphoma is associatedwith exposure to pesticides. In some embodiments of a method of treatingT-cell lymphoma, the T-cell lymphoma is associated with use ofimmunosuppressant drugs. In some embodiments of a method of treatingT-cell lymphoma, the T-cell lymphoma is associated with weakened immunesystem. In some embodiments of a method of treating T-cell lymphoma, theT-cell lymphoma is associated with genetic disorders. In someembodiments of a method of treating T-cell lymphoma, the T-cell lymphomais associated with previous chemotherapy. In some embodiments of amethod of treating T-cell lymphoma, the T-cell lymphoma is associatedwith previous radiation therapy.

In some embodiments of a method of treating T-cell lymphoma, thetreatment of T-cell lymphoma in a subject in need thereof comprises thesteps of: (a) identifying a subject in need of treatment of T-celllymphoma, and (b) administering a therapeutically effective amount of abridged ETP compound to said subject, thereby treating the T-celllymphoma.

In some embodiments of a method of treating T-cell lymphoma, the methodfurther comprises administering an additional therapeutic agent. In someembodiments, the additional therapeutic agent is alemtuzumab,bendamustine, bexarotene, bleomycin, bortezomib, brentuximab vedotin,carboplatin, carfilzomib, carmustine, cisplatin, cyclophosphamide,cytarabine, dacarbazine, dazatinib, denileukin diftitox, dexamethasone,doxorubicin, etoposide, everolimus, fludarabine, forodesine,gemcitabine, hydroxydaunorubicin, ifosfamide, imiquimod, interferons,lenalidomide, liposomal doxorubicin, mechlorethamine, methotrexate,methylprednisolone, nelfinavir, oral corticosteroids, panobinostat,pentostatin, pralatrexate, prednisone, prednisolone, psoralen,retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus,topical corticosteroids, vinblastine, vincristine, vinorelbine,vorinostat, or a combination thereof.

In some embodiments of a method of treating T-cell lymphoma, thetreatment of T-cell lymphoma in a subject in need thereof results inreduction or minimization of undesired side effects in the subjectassociated with chemotherapy, chemotherapy, radiotherapy, or cancertherapy. In some embodiments, the undesired side effects in the subjectassociated with chemotherapy, chemotherapy, radiotherapy, or cancertherapy comprise fatigue, anemia, appetite changes, bleeding problems,diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheralneuropathy, swelling, skin and nail changes, urinary and bladderchanges, and trouble swallowing.

Embodiments P

Embodiment P1. A method for treating T-cell lymphoma in a subject inneed thereof, comprising administering to the subject, a compound havingthe structure of formula (I):

-   -   wherein,    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C),        —NO₂, —SR^(1D), —SO_(n1)R^(1B), SO_(n1)OR^(1B),        —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), ONR^(1B)R^(1C),        —NHC(O)NHNR^(1B)R^(1C)-substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(2A), —NR^(2B)R^(2C)—COOR^(2A), —CONR^(2B)R^(2C),        —NO₂, —SR^(2D), SO_(n2)R^(2B), SO_(n2)OR^(2B),        —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),        —NHC(O)NHNR^(2B)R^(2C)-substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO₃R^(3B), —SO_(n3)OR^(3B),        —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),        —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(4A), —NR³⁴R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂,        —SR^(4D), —SO_(n4)R^(4B), —SO_(n4)OR^(4B),        —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),        —NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(5A), —NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C),        —NO₂, —SR^(5D), SO_(n5)R^(5B), SO_(n5)OR^(5B),        SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), ONR^(5B)R^(5C),        NHC(O)NHNR^(5B)R^(5C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, SR^(6D), SO_(n6)R^(6B), SO_(n6)OR^(6B),        SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), ONR^(6B)R^(6C),        NHC(O)NHNR^(6B)R^(6C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(16A), —NR^(16B)R^(6C), —COOR^(16A),        —CONR^(16B)R^(16C), —NO₂, —SR^(16D), —SO_(n16)R^(16B),        —SO_(n16)OR^(16B), —SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C),        —ONR^(16B)R^(16C), —NHC(O)NHNR^(16B)R^(16C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(18A), —NR^(18B)R^(18C), —COOR^(18A),        —CONR^(18B)R^(18C), —NO₂, —SR^(18D), —SO₁₈R^(8B),        —SO_(n18)OR^(10B), —SO_(v18)NR^(18B)R^(18C), NHNR^(18B)R^(18C),        ONR^(18B)R^(18C), NHC(O)NHNR^(18B)R^(18C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C)        and R^(18D) are independently hydrogen, —CX₃, —CN, —COOH,        —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   X is independently —F, —Cl, —Br, or —I;    -   n1, n2, n3, n4, n5, n6, n16, and n18 are an integer from 0 to 4;    -   v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;        and    -   p is 2, 3, or 4;        or a pharmaceutically acceptable salt thereof.

Embodiment P2. The method of Embodiment P1, wherein R¹⁸ is substitutedor unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment P3. The method of anyone of Embodiments P1-P2, wherein R¹⁶ ishydrogen.

Embodiment P4. The method of anyone of Embodiments P1-P3, wherein R³ andR⁴ are independently hydrogen or methyl.

Embodiment P5. The method of anyone of Embodiments P1-P4, wherein R¹ is—CN, —COOR^(1A), —CONR^(1B)R^(1C), or substituted or unsubstitutedheteroalkyl.

Embodiment P6. The method of anyone of Embodiments P1-P5, wherein R¹ is—CN.

Embodiment P7. The method of anyone of Embodiments P1-P6, wherein R² is—CF₃, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl.

Embodiment P8. The method of anyone of Embodiments P1-P7, wherein R² issubstituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl

Embodiment P9. The method of any one of Embodiments P1-P8, wherein R² ismethyl or methoxy.

Embodiment P10. The method of anyone of Embodiments P1-P9, wherein R⁵and R⁶ are independently hydrogen, halogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted cycloalkyl.

Embodiment P11. The method of anyone of Embodiments P1-P10, wherein R⁵and R⁶ are independently hydrogen, methyl, ethyl, allyl, or cyclopropyl.

Embodiment P12. The method of anyone of Embodiments P1-P11, wherein R⁵and R⁶ are independently hydrogen or methyl.

Embodiment P13. The method of anyone of Embodiments P1-P12, wherein p is2.

Embodiment P14. The method of Embodiment P1, wherein the compound offormula (I) has the structure of formula (II):

-   -   wherein,    -   X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)— or —S—;    -   X² is —CR^(22A)R^(22B), —O— NR^(22C)— or —S—;    -   R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C),        —NO₂, —SR^(7D), —SO_(n7)R^(7B), —SO_(n7)OR^(7B),        —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),        —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A),        CONR^(10B)R^(10C), —NO₂, —SR^(10D), —SO_(n10)R^(10B),        —SO_(n10)OR^(10B), —SO_(v10)NR^(10B)R^(10C), —NR^(10B)R^(10C),        —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(11A), —NR^(11B)R^(11C), —COOR^(11A),        —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),        —SO_(n11)OR^(11B), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),        —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁰ and R¹¹ are optionally joined together to form a substituted        or unsubstituted cycloalkyl, a substituted or unsubstituted        heterocycloalkyl, a substituted or unsubstituted aryl, or a        substituted or unsubstituted heteroaryl;    -   R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(12A), —NR^(12B)R^(12C)—COOR^(12A),        —CONR^(12B)R^(12C), —NO₂, —SR^(12D)D, —SO_(n12)R^(12B),        —SO_(n12)OR^(12B), SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C),        ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(13A),        —CONR^(13B)R^(13C), —NO₂, —SR^(13D), SO_(n13)R^(13B),        —SO_(n13)OR^(13B), —SO_(v13)NR^(13B)R^(13C), —NHNR^(13B)R^(13C),        —ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(21A), R^(21B), R^(22A), and R^(22B), are independently        hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,        —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,        —OCHBr₂, —OCHI₂, —OCHF₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(7A), R^(7B), R^(7C), R^(7C), R^(10A), R^(10B), R^(10C),        R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(12A), R^(12B),        R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D), R^(21C)        and R^(22C) are independently hydrogen, —CX₃, —CN, —COOH,        —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   n7, n10, n11, n12 and n13 are independently 0 or 4;    -   v7, v10, v11, v12 and v13 are independently 1 or 2; and    -   p is 2 or 3;        or a pharmaceutically acceptable salt thereof.

Embodiment P15. The method of Embodiment P14, wherein the compound offormula (II) has the structure of formula:

Embodiment P16. The method of Embodiment P15, wherein X¹ and X² areindependently —O— or —S—.

Embodiment P17. The method of Embodiment P15, wherein p is 2.

Embodiment P18. The method of Embodiment P15, wherein the compound offormula (II(S)) has the structure of formula (III(S)):

Embodiment P19. The method of Embodiment P18, wherein R¹ is —CN,—OR^(1A), —COOR^(1A), or —CONR^(1B)R^(1C), and wherein R^(1A), R^(1B),and R^(1C) are independently hydrogen, or substituted or unsubstitutedalkyl.

Embodiment P20. The method of Embodiment P18 or P19, wherein R¹ is —CN.

Embodiment P21. The method of anyone of Embodiments P18-P20, wherein R²is —CF₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl.

Embodiment P22. The method of anyone of Embodiments P18-P21, wherein R²is substituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment P23. The method of anyone of Embodiments P18-P22, wherein R²is methyl.

Embodiment P24. The method of anyone of Embodiments 19-24, wherein R³and R⁴ are hydrogen.

Embodiment P25. The method of anyone of Embodiments P18-P24, wherein R¹²and R¹³ are independently hydrogen or methyl.

Embodiment P26. The method of anyone of Embodiments P18-P25, wherein R¹⁰and R¹¹ are hydrogen.

Embodiment P27. The method of any one of Embodiments P1-P14, wherein thecompound has the structure of formula:

Embodiment P28. The method of Embodiment P18, wherein the compound hasthe structure of formula:

Embodiment P29. The method of any one of Embodiments P1-P28, wherein theT-cell lymphoma is cutaneous T-cell lymphoma (CTCL), peripheral T-celllymphoma, anaplastic large-cell lymphoma, angioimmunoblastic T-celllymphoma, adult T-cell Leukemia/Lymphoma, blastic natural killer (NK)cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenicT-cell lymphoma, lymphoblastic lymphoma, or nasal natural killer(NK)/T-cell lymphoma.

Embodiment P30. The method of Embodiment P29, wherein the cutaneousT-cell lymphoma is Sezary syndrome, mycosis fungoides, folliculotropicmycosis fungoides, pagetoid reticulosis, granulomatous slack skin,primary cutaneous CD30+ T-cell lymphoproliferative disorders,lymphomatoid papulosis, primary cutaneous anaplastic large-celllymphoma, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+aggressive epidermotropic lymphoma, primary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphoma, or primary cutaneous CD4+small/medium T-cell lymphoma.

Embodiment P31. The method of anyone of Embodiments P1-P30, wherein theT-cell lymphoma is associated with at least one of the followingconditions: smoking, obesity, infection, HIV, Epstein-Barr virus, humanT-lymphotropic virus, Helicobacter pyroli infection, chronicHelicobacter pyroli infection, exposure to chemicals, exposure toinsecticides, exposure to pesticides, use of immunosuppressant drugs,weakened immune system, genetic disorders, previous chemotherapy, andprevious radiation therapy.

Embodiment P32. The method of any one of Embodiments P1-P31, furthercomprising administering to the subject an additional therapeutic agentused in the treatment of T-cell lymphoma.

Embodiment P33. The method of Embodiment P32, wherein the additionaltherapeutic agent is alemtuzumab, bendamustine, bexarotene, bleomycin,bortezomib, brentuximab vedotin, carboplatin, carfilzomib, carmustine,cisplatin, cyclophosphamide, cytarabine, dacarbazine, dazatinib,denileukin diftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate, prednisone,prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof.

Embodiment P34. A pharmaceutical composition for treating T-celllymphoma comprising an ETP derivative, at least one additionaltherapeutic agent used in the treatment of T-cell lymphoma, and at leastone pharmaceutically acceptable excipient.

Embodiment P35. The pharmaceutical composition of Embodiment P34,wherein the ETP derivative is a compound having the structure of formula(I):

-   -   wherein,    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C),        —NO₂, —SR^(1D), —SO_(n1)R^(1B), —SO_(n1)OR^(1B),        —SO_(n1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),        NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C),        —NO₂, —SR^(2D), —SO_(n2)R^(2B), —SO_(n2)OR^(2B),        —SO_(n2)NR^(2B)R^(2C), R^(2B)R^(2C), —ONR^(2B)R^(2C),        NHC(O)NHNR^(2B)R^(2C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO_(n3)R^(3B), —SO_(n3)OR^(3B),        —SO_(n3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),        —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(4A), —NR³⁴R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂,        —SR^(4D), —SO_(n4)R^(4B), —SO_(n4)OR^(4B),        —SO_(n4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), ONR^(4B)R^(4C),        —NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(5A), —NR^(1B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C),        —NO₂, SR^(5D), SO_(n5)R^(5B), —SO_(n5)OR^(5B),        —SO_(n5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),        NHC(O)NHNR^(5B)R^(5C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, —SR^(6D), —SO_(n6)R^(6B), —SO_(n16)OR^(6B),        —SO_(n6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), ONR^(6B)R^(6C),        NHC(O)NHNR^(6B)R^(6C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(16B)R^(16C), COOR^(16A), —CONR^(16B)R^(6C),        —NO₂, —SR^(16D), —SO_(n16)R^(16B), SO_(n16)OR^(16B),        —SO_(n16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C), —ONR^(16B)R^(16C),        —NHC(O)NHNR^(16B)R^(16C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(18A), —NR^(18B)R^(18C), —COOR^(18A),        —CONR^(18B)R^(18C), —NO₂, —SR^(18D), —SO_(n18)OR^(18B),        —SO_(n18)OR^(18B), —SO_(n18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C),        —ONR^(18B)R^(18C), —NHC(O)NHNR^(18B)R^(18C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C),        and R^(18D) are independently hydrogen, —CX₃, —CN, —COOH,        —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   X is independently —F, —Cl, —Br, or —I;    -   n1, n2, n3, n4, n5, n6, n16, and n18 are an integer from 0 to 4;    -   v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;        and    -   p is 2, 3, or 4;        or a pharmaceutically acceptable salt thereof.

Embodiment P36. The pharmaceutical composition of Embodiments P34-P35,wherein the additional therapeutic agent is alemtuzumab, bendamustine,bexarotene, bleomycin, bortezomib, brentuximab vedotin, carboplatin,carfilzomib, carmustine, cisplatin, cyclophosphamide, cytarabine,dacarbazine, dazatinib, denileukin diftitox, dexamethasone, doxorubicin,etoposide, everolimus, fludarabine, forodesine, gemcitabine,hydroxydaunorubicin, ifosfamide, imiquimod, interferons, lenalidomide,liposomal doxorubicin, mechlorethamine, methotrexate,methylprednisolone, nelfinavir, oral corticosteroids, panobinostat,pentostatin, pralatrexate, prednisone, prednisolone, psoralen,retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus,topical corticosteroids, vinblastine, vincristine, vinorelbine,vorinostat, or a combination thereof.

Embodiments Q

Embodiment Q1. A method for treating T-cell lymphoma in a subject inneed thereof, comprising administering to the subject, a compound havingthe structure of formula (XXI):

-   -   wherein,    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C),        —NO₂, —SR^(1D), —SO_(n1)R^(1B), —SO_(n1)OR^(1B),        —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),        —NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(2A), —NR^(2B)R^(2C)—COOR^(2A), —CONR^(2B)R^(2C),        —NO₂, —SR^(2D), —SO_(n2)R^(2B), —SO_(n2)OR^(2B),        —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),        —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C)—COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO_(n3)R^(3B), —SO_(n3)OR^(3B),        —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),        —NHC(O)NHNR^(3B)R^(3C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(4A), —NR³⁴R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂,        —SR^(4D), —SO_(n4)R^(4B), —SO_(n4)OR^(4B),        —SO_(v4)NR^(4B)R^(4C), NHNR^(4B)R^(4C), ONR^(4B)R^(4C),        NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(5A), —NHNR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C),        —NO₂, —SR^(5D), —SO_(n5)R^(5B), —SO_(n5)OR^(5B),        —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), ONR^(5B)R^(5C),        NHC(O)NHNR^(5B)R^(5C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, —SR^(6D), —SO_(n6)R^(6B), —SO_(n6)OR^(6B),        —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), ONR^(6B)R^(6C),        NHC(O)NHNR^(6B)R^(6C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(16A), —NR^(16B)R^(16C), —COOR^(16A),        —CONR^(16B)R^(16C), —NO₂, —SR^(16D), —SO_(n16)R^(16B),        —SO_(n16)OR^(16B), —SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C),        ONR^(16B)R^(16C), NHC(O)NHNR^(16B)R^(16C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(18A), —NR^(18B)R^(18C), —COOR^(18A),        —CONR^(18B)R^(18C), —NO₂, —SR^(18D), —SO_(n18)R^(18B),        —SO_(n18)OR^(18B), —SO_(v18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C),        —ONR^(18B)R^(18C), —NHC(O)NHNR^(18B)R^(18C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R²⁵ is hydrogen —C(O)-L¹-R³², —C(S)-L¹-R³², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R²⁶ is hydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R²⁵ and R²⁶ may optionally be joined to form

-   -   L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   R³² and R³³ are independently halogen, substituted or        unsubstituted C₁-C₃ alkyl, substituted or unsubstituted aryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C),        and R^(18D) are independently hydrogen, halogen, —CX₃, —CN,        —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   X is independently —F, —Cl, —Br, or —I;    -   n1, n2, n3, n4, n5, n6, n16, and n18 are independently an        integer from 0 to 4;        and    -   v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;        or a pharmaceutically acceptable salt thereof.

Embodiment Q2. The method of Embodiment Q1, wherein R¹⁸ is substitutedor unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment Q3. The method of Embodiment Q1 or Q2, wherein R¹⁶ ishydrogen.

Embodiment Q4. The method of Embodiment Q1, wherein the compound has theformula:

-   -   wherein:    -   X³ is —N═ or —CR⁷═;    -   X⁴ is —N═ or —CR⁸═;    -   X⁵ is —N═ or —CR⁹═;    -   R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C),        —NO₂, —SR^(7D), —SO_(n7)R^(7B), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C),        —NO₂, —SR^(8D), —SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁷ and R⁸ may optionally be joined to form a substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl;    -   R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C),        —NO₂, —SR^(9D), —SO_(v9)R^(9B), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁸ and R⁹ may optionally be joined to form a substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl;    -   R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A),        —CONR^(10B)R^(10C), —NO₂, —SR^(10D), —SO_(n10)R^(10B),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), ONR^(10B)R^(10C),        NHC(O)NHNR^(10B)R^(10C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(11A), —NR^(11B)R^(11C), —COOR^(11A),        —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),        —SO_(v11)NR^(11B)R^(11C), —R^(11B)R^(11C), —ONR^(11B)R^(11C),        NHC(O)NHNR^(11B)R^(11C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D),        R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),        R^(10D), R^(11A), R^(11B), R^(11C) and R^(11D) are independently        hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R^(7B) and R^(7C), R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B)        and R^(10C), and R^(11B) and R^(11C), substituents bonded to the        same nitrogen atom may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl or substituted or        unsubstituted heteroaryl; n7, n8, n9, n10 and n11 are        independently an integer from 0 to 4; and v7, v8, v9, v10 and        v11 are independently 1 or 2.

Embodiment Q5. The method of any one of Embodiments Q2 to Q4, wherein R⁷and R⁸ or R⁸ and R⁹ are joined to form a substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl havingstructural formula:

-   -   wherein:    -   X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)— or —S—;    -   X² is —CR^(22A)R^(22B)—, —O—, —NR^(22C)—, or —S—;    -   R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(12A), —NR^(12B)R^(12C), —COOR^(12A),        CONR^(12B)R^(12C), —NO₂, —SR^(12D), —SO_(n12)R^(12B),        —SO_(n12)OR^(12B), SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C),        ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(3A),        —CONR^(13B)R^(13C), —NO₂, —SR^(13D), —SO_(n13)R^(3B),        —SO_(v12)OR^(13B), —SO_(v12)NR^(13B)R^(13C), —NHNR^(13B)R^(13C),        —ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R²⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(27A), —NR^(27B)R^(27C), COOR^(27A),        —CONR^(27B)R^(27C), —NO₂, —SR^(27D), —SO_(n27)R^(27B),        —SO_(n27)OR^(27B), —SO_(v27)NR^(27B)R^(27C), —NHNR^(27B)R^(27C),        —ONR^(27B)R^(27C), NHC(O)NHNR^(27B)R^(27C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R^(21A), R^(21B), R^(22A), and R^(22B) are independently        hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,        —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,        —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl, substituted        or unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R^(21C), R^(22C), R^(27A), R^(27B), R^(27C), and R^(27D) are        independently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂,        —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   n12, n13, and n27 are independently an integer from 0 to 4;    -   v12, v13 and v27 are independent 1 or 2;    -   m is 1 or 2;    -   z5 is an integer from 0 to 8;        or a pharmaceutically acceptable salt thereof.

Embodiment Q6. The method of any one of Embodiments Q1-Q5, wherein thecompound has the formula:

Embodiment Q7. The method of any one of Embodiments Q1-Q5, wherein thecompound has the formula:

Embodiment Q8. The method of any one of Embodiments Q1-Q6, wherein thecompound has the formula:

Embodiment Q9. The method of any one of Embodiments Q1-Q5, wherein thecompound has the formula:

Embodiment Q10. The method of any one of Embodiments Q1-Q9, wherein thecompound is

Embodiment Q11. The method of any one of Embodiments Q1-Q5, wherein thecompound has the formula:

Embodiment Q12. The method of any one of Embodiments Q1-Q11, wherein thecompound has the formula:

Embodiment Q13. The method of any one of Embodiments Q1-Q5, wherein thecompound has the formula:

-   -   wherein:    -   X⁶ is —N═ or —CR^(23A)═;    -   X⁷ is —CR^(24A)R^(24B)—, —S—, —O—, or —NR^(24C)—;    -   R¹⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(19A), —NR^(19B)R^(19C), —COOR^(19A),        —CONR^(19B)R^(19C), —NO₂, —SR^(19D), —SO_(n19)R^(19B),        —SO_(v19)NR^(19B)R^(19C), —NR^(19B)R^(19C)C, ONR^(19B)R^(19C),        —NHC(O)NHNR^(19B)R^(19C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R²⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(20A), —NR^(20B)R^(20C), COOR^(20A),        CONR^(20B)R^(20C), —NO₂, —SR^(20D), —SO_(n20)R^(20B),        —SO_(v20)NR^(20B)R^(20C), —NHNR^(20B)R^(20C), ONR^(20B)R^(20C),        —NHC(O)NHNR^(20B)R^(20C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(23A), R^(24A), and R^(24B) are independently hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,        —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂,        —OCHI₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C),        R^(20D), and R^(24C) are independently hydrogen, halogen, —CX₃,        —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   n19 and n20 are independently an integer from 0 to 4; and        v19 and v20 are independent 1 or 2.

Embodiment Q14. The method of any one of Embodiments Q1-Q13, wherein thecompound has the formula:

Embodiment Q15. The method of anyone of Embodiments Q1-Q12, wherein R¹⁰and R¹¹ are independently hydrogen.

Embodiment Q16. The method of anyone of Embodiments Q2-Q6, wherein X⁴ is—N═.

Embodiment Q17. The method of anyone of Embodiments Q2-Q6, wherein R⁹ is—OCH₃.

Embodiment Q18. The method of anyone of Embodiments Q1-Q17, wherein R²is substituted or unsubstituted alkyl.

Embodiment Q19. The method of anyone of Embodiments Q1-Q18, wherein R²is substituted or unsubstituted C₁-C₃ alkyl.

Embodiment Q20. The method of anyone of Embodiments Q1-Q19, wherein R²is methyl.

Embodiment Q21. The method of anyone of Embodiments Q1-Q17, wherein R²is substituted or unsubstituted alkyl.

Embodiment Q22. The method of anyone of Embodiments Q1-Q21, wherein R¹is —CN.

Embodiment Q23. The method of any one of Embodiments Q1-Q22, wherein:

-   -   R²⁵ is —C(O)-L¹-R³² or —C(S)-L¹-R³²; and    -   R²⁶ is —C(O)-L²-R³³ or —C(S)-L²-R³³.

Embodiment Q24. The method of any one of Embodiments Q1-Q23, wherein Land L² are independently a bond, —O—, or —NH—.

Embodiment Q25. The method of any one of Embodiments Q1-Q23, wherein:

-   -   L¹ is -L^(1A)-L^(1B), wherein L^(1A) is bonded to —C(O)— or        —C(S)—; and    -   L² is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to —C(O)— or        —C(S)—;    -   L^(1A) is a bond or —(CH₂)_(z1)—;    -   L^(1B) is a bond, —O— or —NR^(30B)—;    -   L^(2A) is a bond or —(CH₂)_(z2)—;    -   L^(2B) is a bond, —O— or —NR^(31B)—;    -   z1 and z2 are independently an integer from 1 to 10; and    -   R^(30B) and R^(31B) are independently hydrogen or substituted or        unsubstituted alkyl.

Embodiment Q26. The method of Embodiment Q25, wherein L^(1A) and L^(2A)are independently —CH₂—.

Embodiment Q27. The method of Embodiment Q25 or Q26, wherein:

-   -   L^(1B) is —NR^(30B)—.    -   L^(2B) is —NR^(31B)—; and    -   R^(30B) and R^(31B) are independently unsubstituted C₁-C₃ alkyl.

Embodiment Q28. The method of anyone of Embodiments Q1-Q27, wherein R³²and R³³ are independently unsubstituted C₁-C₃ alkyl or unsubstitutedaryl.

Embodiment Q29. The method of any one of Embodiments Q1 to Q28, whereinR³² and R³³ are independently halogen.

Embodiment Q30. The method of any one of Embodiments Q1 to Q21, whereinR²⁵ and R²⁶ are joined together to form:

Embodiment Q31. The method of anyone of Embodiments Q1-Q30, wherein R⁶is methyl.

Embodiment Q32. The method of any one of Embodiments Q1-Q31, wherein thecompound has the structure:

Embodiment Q33. The method of any one of Embodiments Q1-Q32, wherein theT-cell lymphoma is cutaneous T-cell lymphoma (CTCL), peripheral T-celllymphoma, anaplastic large-cell lymphoma, angioimmunoblastic T-celllymphoma, adult T-cell Leukemia/Lymphoma, blastic natural killer (NK)cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenicT-cell lymphoma, lymphoblastic lymphoma, or nasal natural killer(NK)/T-cell lymphoma.

Embodiment Q34. The method of Embodiment Q33, wherein the cutaneousT-cell lymphoma is Sezary syndrome, mycosis fungoides, folliculotropicmycosis fungoides, pagetoid reticulosis, granulomatous slack skin,primary cutaneous CD30+ T-cell lymphoproliferative disorders,lymphomatoid papulosis, primary cutaneous anaplastic large-celllymphoma, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+aggressive epidermotropic lymphoma, primary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphoma, or primary cutaneous CD4+small/medium T-cell lymphoma.

Embodiment Q35. The method of anyone of Embodiments Q1-Q34, wherein theT-cell lymphoma is associated with at least one of the followingconditions: smoking, obesity, infection, HIV, Epstein-Barr virus, humanT-lymphotropic virus, Helicobacter pyroli infection, chronicHelicobacter pyroli infection, exposure to chemicals, exposure toinsecticides, exposure to pesticides, use of immunosuppressant drugs,weakened immune system, genetic disorders, previous chemotherapy, andprevious radiation therapy.

Embodiment Q36. The method of any one of Embodiments Q1-Q35, furthercomprising administering to the subject an additional therapeutic agentused in the treatment of T-cell lymphoma.

Embodiment Q37. The method of Embodiment Q36, wherein the additionaltherapeutic agent is alemtuzumab, bendamustine, bexarotene, bleomycin,bortezomib, brentuximab vedotin, carboplatin, carfilzomib, carmustine,cisplatin, cyclophosphamide, cytarabine, dacarbazine, dazatinib,denileukin diftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate, prednisone,prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof.

Embodiment Q38. A pharmaceutical composition for treating T-celllymphoma comprising an ETP derivative, at least one additionaltherapeutic agent used in the treatment of T-cell lymphoma, and at leastone pharmaceutically acceptable excipient.

Embodiment Q39. The pharmaceutical composition of Embodiment Q38,wherein the ETP derivative is a compound having the structure of formula(XXI):

-   -   wherein,    -   R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C),        —NO₂, —SR^(1D), —SO_(n1)R^(1B), —SO_(n1)OR^(1B),        —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), ONR^(1B)R^(1C),        NHC(O)NHNR^(1B)R^(1C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C),        —NO₂, —SR²-D, —SO_(n2)R^(2B), —SO_(n2)OR^(2B),        —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),        —NHC(O)NHNR^(2B)R^(2C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(3A), —NR^(3B)R^(3C)—COOR^(3A), —CONR^(3B)R^(3C),        —NO₂, —SR^(3D), —SO₃R^(3B), —SO_(n3)OR^(3B),        —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),        NHC(O)NHNR^(3B)R^(3C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(4A), —NR³⁴R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂,        —SR^(4D), —SO_(n4)R^(4B), SO_(n4)OR^(4B), —SO_(v4)NR^(4B)R^(4C),        —NHNR^(4B)R^(4C), ONR^(4B)R^(4C), NHC(O)NHNR^(4B)R^(4C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(5A), —NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C),        —NO₂, —SR^(5D), —SO_(n5)R^(5B), SO_(n5)OR^(5B),        —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), ONR^(5B)R^(5C),        —NHC(O)NHNR^(5B)R^(5C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C),        —NO₂, —SR^(6D), —SO_(n6)R^(6B), —SO_(n6)OR^(6B),        —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), ONR^(6B)R^(6C),        NHC(O)NHNR^(6B)R^(6C), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(6A), —NR^(16B)R^(16C), COOR^(16A),        —CONR^(16B)R^(16C), —NO₂, —SR^(16D), —SO_(n16)R^(16B),        SO_(n16)OR^(16B), —SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C),        —ONR^(16B)R^(16C), —NHC(O)NHNR^(16B)R^(16C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(18A), —NR^(18B)R^(18C), —COOR^(18A),        —CONR^(18B)R^(18C), —NO₂, —SR^(18D), —SO_(n18)R^(18B),        —SO_(n18)OR^(18B), —SO_(v18)NR^(18B)R^(18C), —NHNR¹⁸R^(18C),        —ONR^(18B)R^(18C), —NHC(O)NHNR^(18B)R^(18C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R²⁵ is hydrogen —C(O)-L¹-R³², —C(S)-L¹-R³², substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R²⁶ is hydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R²⁵ and R²⁶ may optionally be joined to form

-   -   L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,        substituted or unsubstituted heteroalkylene;    -   R³² and R³³ are independently halogen, substituted or        unsubstituted C₁-C₃ alkyl, substituted or unsubstituted aryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D)D,        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(16A), R^(16B), R^(16C), R^(16D), R^(18A), R^(18B), R^(18C),        and R^(18D) are independently hydrogen, halogen, —CX₃, —CN,        —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   X is independently —F, —Cl, —Br, or —I;    -   n1, n2, n3, n4, n5, n6, n16, and n18 are independently an        integer from 0 to 4;        and    -   v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;        or a pharmaceutically acceptable salt thereof.

Embodiment Q40. The pharmaceutical composition of Embodiment Q38 or Q39,wherein the additional therapeutic agent is alemtuzumab, bendamustine,bexarotene, bleomycin, bortezomib, brentuximab vedotin, carboplatin,carfilzomib, carmustine, cisplatin, cyclophosphamide, cytarabine,dacarbazine, dazatinib, denileukin diftitox, dexamethasone, doxorubicin,etoposide, everolimus, fludarabine, forodesine, gemcitabine,hydroxydaunorubicin, ifosfamide, imiquimod, interferons, lenalidomide,liposomal doxorubicin, mechlorethamine, methotrexate,methylprednisolone, nelfinavir, oral corticosteroids, panobinostat,pentostatin, pralatrexate, prednisone, prednisolone, psoralen,retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus,topical corticosteroids, vinblastine, vincristine, vinorelbine,vorinostat, or a combination thereof.

EMBODIMENTS

Embodiment 1. A method for treating T-cell lymphoma in a subject in needthereof, comprising administering to the subject, a compound having thestructure of formula (1):

wherein,

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂, —SR^(1D),—SO_(n1)R^(1B), —SO_(n1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(2A), —NR^(2B)R^(2C), —COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR²-D,—SO_(n2)R^(2B), —SO_(n2)OR^(2B), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C)—COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C), NHNR^(3B)R^(3C),ONR^(3B)R^(3C), NHC(O)NHNR^(3B)R^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂, —SR^(4D),—SO_(n4)R^(4B), —SO_(n4)OR^(4B), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C), —NO₂, —SR^(5D),SO_(n5)R^(5B), SO_(n5)OR^(5B), SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),ONR^(5B)R^(5C), NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂, —SR^(6D),—SO_(n6)R^(6B), —SO_(n6)OR^(6B), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), ONR^(6B)R^(6C), NHC(O)NHNR^(6B)R^(6C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(16A), —NR^(16B)R^(16C), COOR^(16A), —CONR^(16B)R^(16C), —NO₂,—SR^(16D), —SO_(n16)R^(16B), —SO_(n16)OR^(16B),—SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C), —ONR^(16B)R^(16C),—NHC(O)NHNR^(16B)R^(16C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(18A), —NR^(18B)R^(18C), —COOR^(18A), —CONR^(18B)R^(18C), —NO₂,—SR^(18D), —SO_(n18)R^(18B), —SO_(n18)OR^(18B),—SO_(v18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C), ONR^(18B)R^(18C),—NHC(O)NHNR^(18B)R^(18C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶, wherein R²⁸ and R²⁹ are optionally joinedto form *—S_(p)—* wherein p is an integer from 2 to 4 and each *represents the point of attachment to the remainder of the compound;

R²⁵ is hydrogen, —C(O)-L¹-R³², —C(S)-L¹-R³², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R²⁶ is hydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R²⁵ and R²⁶ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;

L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;

R³² and R³³ are independently halogen, substituted or unsubstitutedC₁-C₃ alkyl, substituted or unsubstituted aryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B),R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), and R^(18D) areindependently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; X is independently —F, —Cl,—Br, or —I;

n1, n2, n3, n4, n5, n6, n16, and n18 are independently an integer from 1to 4; and

v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;

or a pharmaceutically acceptable salt thereof.

Embodiment 2. The method of Embodiment 1, wherein R¹⁸ is substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment 3. The method of Embodiment 1, wherein R¹⁶ is hydrogen.

Embodiment 4. The method of Embodiments 1-3, wherein the compound havingthe structure of formula (I):

Embodiment 5. The method of Embodiment 4, wherein R³ and R⁴ areindependently hydrogen or unsubstituted methyl.

Embodiment 6. The method of Embodiments 4-5, wherein R is —CN,—COOR^(1A), —CONR^(1B)R^(1C), or substituted or unsubstitutedheteroalkyl.

Embodiment 7. The method of Embodiments 4-6, wherein R¹ is —CN.

Embodiment 8. The method of Embodiments 4-7, wherein R² is —CF₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl.

Embodiment 9. The method of Embodiments 4-8, wherein R² is substitutedor unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

Embodiment 10. The method of Embodiments 4-9, wherein R² is methyl ormethoxy.

Embodiment 11. The method of Embodiments 4-10, wherein R⁵ and R⁶ areindependently hydrogen, halogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted cycloalkyl.

Embodiment 12. The method of Embodiments 4-11, wherein R⁵ and R⁶ areindependently hydrogen, methyl, ethyl, allyl, or cyclopropyl.

Embodiment 13. The method of Embodiments 4-12, wherein R⁵ and R⁶ areindependently hydrogen or unsubstituted methyl.

Embodiment 14. The method of Embodiments 4-13, wherein p is 2.

Embodiment 15. The method of Embodiment 4, wherein the compound offormula (I) has the structure of formula (II):

wherein,

X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)— or —S—;

X² is —CR^(22A)R^(22B)—, —O—, —NR^(22C)—, or —S—;

R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),SO_(n7)R^(7B), SO_(n7)OR^(7B), SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C), —NO₂,—SR^(10D), —SO_(n10)R^(10B), —SO_(n10)OR^(10B),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), CONR^(11B)R^(11C), —NO₂,—SR^(11D), —SO_(n11)R^(11B), —SO_(n11)OR^(11B),—SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C), —ONR^(11B)R^(11C),—NHC(O)NHNR^(11B)R^(11C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁰ and R¹¹ are optionally joined together to form a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl;

R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(12A), —NR^(12B)R^(12C), —COOR^(12A), CONR^(12B)R^(12C), —NO₂,—SR^(12D), —SO_(n12)R^(12B), —SO_(n12)OR^(12B),—SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C), —ONR^(12B)R^(12C),—NHC(O)NHNR^(12B)R^(12C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), —CONR^(13B)R^(13C), —NO₂,—SR^(13D), —SO_(n13)R^(13B), —SO_(n13)OR^(13B),—SO_(v13)NR^(13B)R^(13C), —NHNR^(13B)R^(13C), —ONR^(13B)R^(13C),—NHC(O)NHNR^(13B)R^(13C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(21A), R^(21B), R^(22A), and R^(22B), are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R^(7A), R^(7B), R^(7C), R^(7C), R^(10A), R^(10B), R^(10C), R^(10D),R^(11A), R^(11B), R^(11C), R^(11D), R^(12A), R^(12B), R^(12C), R^(12D),R^(13A), R^(13B), R^(13C), R^(13D), R^(21C), and R^(22C) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

n7, n10, n11, n12 and n13 are independently 1 or 4;

v7, v10, v11, v12 and v13 are independently 1 or 2; and

p is 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiment 16. The method of Embodiment 15, wherein the compound offormula (II) has the structure of formula:

Embodiment 17. The method of Embodiment 16, wherein X¹ and X² areindependently —O— or —S—.

Embodiment 18. The method of Embodiments 15-17, wherein p is 2.

Embodiment 19. The method of Embodiments 16-17, wherein the compound offormula (II(S)) has the structure of formula (III(S)):

Embodiment 20. The method of Embodiment 19, wherein R¹ is —CN, —OR^(1A),—COOR^(1A), or —CONR^(1B)R^(1C), and wherein R^(1A), R^(1B), and R^(1C)are independently hydrogen, or substituted or unsubstituted alkyl.

Embodiment 21. The method of Embodiments 19 or 20, wherein R¹ is —CN.

Embodiment 22. The method of Embodiments 19-21, wherein R² is —CF₃,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl.

Embodiment 23. The method of Embodiments 19-22, wherein R² issubstituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment 24. The method of Embodiments 19-23, wherein R² is methyl.

Embodiment 25. The method of Embodiments 19-24, wherein R³ and R⁴ arehydrogen.

Embodiment 26. The method of Embodiments 19-25, wherein R¹² and R¹³ areindependently hydrogen or unsubstituted methyl.

Embodiment 27. The method of Embodiments 19-27, wherein R¹⁰ and R¹¹ arehydrogen.

Embodiment 28. The method of Embodiments 4-27, wherein the compound is:

Embodiment 29. The method of Embodiment 28, wherein the compound is:

Embodiment 30. The method of Embodiments 1-3, a compound having thestructure of formula (XXI):

Embodiment 31. The method of Embodiment 30, wherein the compound has theformula:

wherein:

X³ is —N═ or —CR⁷═;

X⁴ is —N═ or —CR⁸═;

X⁵ is —N═ or —CR⁹═;

R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(8A), —NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂, —SR^(8D),SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷ andR⁸ may optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl;

R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A)—NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), SO_(v9)NR^(9B)R^(9C), —R^(9B)R^(9C)—ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁸ andR⁹ may optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl;

R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), COOR^(10A), CONR^(10B)R^(10C), —NO₂,—SR^(10D), —SO_(n10)R^(10B), SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(11A), —NR^(11B)R^(11C),—COOR^(11A), —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),—SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C), —ONR^(11B)R^(11C),—NHC(O)NHNR^(11B)R^(11C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A),R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A),R^(11B), R^(11C) and R^(11D) are independently hydrogen, halogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(7B) and R^(7C), R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) andR^(10C), and R^(11B) and R^(11C), substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

n7, n8, n9, n10 and n11 are independently an integer from 1 to 4; and

v7, v8, v9, v10 and v11 are independently 1 or 2.

Embodiment 32. The method of Embodiment 31, wherein R⁷ and R⁸ or R⁸ andR⁹ are joined to form a substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl having structural formula:

wherein:

X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)—, or —S—;

X² is —CR^(22A)R^(22B), —O—, —NR^(22C)—, or —S—;

R¹² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(12A), —NR^(12B)R^(12C), COOR^(12A), CONR^(12B)R^(12C), —NO₂,—SR^(12D), —SO_(n2)R^(12B), —SO_(n12)OR^(12B), —SO_(v12)NR^(12B)R^(12C),NHNR^(12B)R^(12C), —ONR^(12B)R^(12C), NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(13B)R^(13C), —COOR^(13A), CONR^(13B)R^(13C), —NO₂,—SR^(13D), —SO_(n13)R^(13B), —SO_(v12)OR^(13B),—SO_(v12)NR^(13B)R^(13C), —NHNR^(13B)R^(13C), —ONR^(13B)R^(13C),—NHC(O)NHNR^(13B)R^(13C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R²⁷ is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(27A),—NR^(27B)R^(27C), —COOR^(27A), —CONR^(27B)R^(27C), —NO₂, SR^(27D),SO_(n27)R^(27B), SO_(n27)OR^(27B), —SO_(v27)NR^(27B)R^(27C),—NHNR^(27B)R^(27C), —ONR^(27B)R^(27C), —NHC(O)NHNR^(27B)R^(27C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R^(21A), R^(21B), R^(22A), and R^(22B) are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R^(21C), R^(22C), R^(27A), R^(27B), R^(27C), and R^(27D) areindependently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

n12, n13, and n27 are independently an integer from 1 to 4;

v12, v13 and v27 are independent 1 or 2;

m is 1 or 2;

z5 is an integer from 0 to 8;

or a pharmaceutically acceptable salt thereof.

Embodiment 33. The method of Embodiments 30-32, wherein the compound hasthe formula:

Embodiment 34. The method of Embodiment 31, wherein the compound has theformula:

Embodiment 35. The method of Embodiment 31, wherein the compound has theformula:

Embodiment 36. The method of Embodiment 31, wherein the compound has theformula:

Embodiment 37. The method of Embodiment 36, wherein the compound is

Embodiment 38. The method of Embodiment 31, wherein the compound has theformula:

Embodiment 39. The method of Embodiment 38, wherein the compound has the

Embodiment 40. The method of Embodiment 30, wherein the compound has theformula:

wherein:

X⁶ is —N═ or —CR^(23A)═;

X⁷ is —CR^(24A)R^(24B)—, —S—, —O—, or —NR^(24C)—.

R¹⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(19A), —NR^(19B)R^(9C), —COOR^(19A), —CONR^(19B)R^(19C), —NO₂,—SR^(19D), —SO_(n19)R^(19B), —SO_(v19)NR^(19B)R^(19C),—NHNR^(19B)R^(19C), —ONR^(19B)R^(19C), —NHC(O)NHNR^(19B)R^(19C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R²⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(20A), —NR^(20B)R^(20C), COOR^(20A), CONR^(20B)R^(20C), —NO₂,—SR^(20D), —SO_(n20)R^(20B), —SO_(v20)NR^(20B)R^(20C),—NHNR^(20B)R^(20C), ONR^(20B)R^(20C), NHC(O)NHNR^(20B)R^(20C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R^(23A), R^(24A), and R^(24B) are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B), R^(20C), R^(20D),and R^(24C) are independently hydrogen, halogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

n19 and n20 are independently an integer from 1 to 4; and

v19 and v20 are independent 1 or 2.

Embodiment 41. The method of Embodiment 40, wherein the compound has theformula:

Embodiment 42. The method of Embodiments 30-39, wherein R¹⁰ and R¹¹ areindependently hydrogen.

Embodiment 43. The method of Embodiments 30-33, wherein X⁴ is —N═.

Embodiment 44. The method of Embodiments 30-33, wherein R⁹ is —OCH₃.

Embodiment 45. The method of Embodiments 30-44, wherein R² issubstituted or unsubstituted alkyl.

Embodiment 46. The method of Embodiments 30-45, wherein R² issubstituted or unsubstituted C₁-C₃ alkyl.

Embodiment 47. The method of Embodiments 30-46, wherein R² is methyl.

Embodiment 48. The method of Embodiments 30-47, wherein R¹ is —CN.

Embodiment 49. The method of Embodiments 30-49, wherein:

R²⁵ is —C(O)-L¹-R³² or —C(S)-L¹-R³²; and

R²⁶ is —C(O)-L²-R³³ or —C(S)-L²-R³³;

Embodiment 50. The method of Embodiments 30-49, wherein L¹ and L² areindependently a bond, —O—, or —NH—;

Embodiment 51. The method of Embodiments 30-49, wherein:

L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) is bonded to —C(O)— or —C(S)—; and

L² is -L^(2A)-L^(2B)-, wherein L^(2A) is bonded to —C(O)— or —C(S)—;

L^(1A) is a bond or —(CH₂)_(z1)—;

L^(1B) is a bond, —O— or —NR^(30B)—;

L^(2A) is a bond or —(CH₂)_(z2)—;

L^(2B) is a bond, —O— or —NR^(31B)—;

z1 and z2 are independently an integer from 30 to 10; and

R^(30B) and R^(31B) are independently hydrogen or substituted orunsubstituted alkyl.

Embodiment 52. The method of Embodiment 51, wherein L^(1A) and L^(2A)are independently —CH₂—.

Embodiment 53. The method of Embodiments 51 or 52, wherein:

L^(31B) is —NR^(30B)—;

L^(2B) is —NR^(31B)—; and

R^(30B) and R^(31B) are independently unsubstituted C₁-C₃ alkyl.

Embodiment 54. The method of Embodiments 30-53, wherein R³² and R³³ areindependently unsubstituted C₁-C₃ alkyl or unsubstituted aryl.

Embodiment 55. The method of Embodiments 30-53, R³² and R³³ areindependently halogen.

Embodiment 56. The method of Embodiments 30-48, wherein R² and R²⁶ arejoined together to form:

Embodiment 57. The method of Embodiments 30-56, wherein R⁶ is methyl.

Embodiment 58. The method of Embodiments 30-57, wherein the compound hasthe structure:

Embodiment 59. The method of Embodiments 1-58, wherein the T-celllymphoma is cutaneous T-cell lymphoma (CTCL), peripheral T-celllymphoma, anaplastic large-cell lymphoma, angioimmunoblastic T-celllymphoma, adult T-cell Leukemia/Lymphoma, blastic natural killer (NK)cell lymphoma, enteropathy-associated T-cell lymphoma, hepatosplenicT-cell lymphoma, lymphoblastic lymphoma, or nasal natural killer(NK)/T-cell lymphoma.

Embodiment 60. The method of Embodiments 59, wherein the cutaneousT-cell lymphoma is Sezary syndrome, mycosis fungoides, folliculotropicmycosis fungoides, pagetoid reticulosis, granulomatous slack skin,primary cutaneous CD30+ T-cell lymphoproliferative disorders,lymphomatoid papulosis, primary cutaneous anaplastic large-celllymphoma, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+aggressive epidermotropic lymphoma, primary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphoma, or primary cutaneous CD4+small/medium T-cell lymphoma.

Embodiment 61. The method of Embodiments 1-60, wherein the T-celllymphoma is associated with at least one of the following conditions:smoking, obesity, infection, HIV, Epstein-Barr virus, humanT-lymphotropic virus, Helicobacter pyroli infection, chronicHelicobacter pyroli infection, exposure to chemicals, exposure toinsecticides, exposure to pesticides, use of immunosuppressant drugs,weakened immune system, genetic disorders, previous chemotherapy, andprevious radiation therapy.

Embodiment 62. The method of Embodiments 1-61, further comprisingadministering to the subject an additional therapeutic agent used in thetreatment of T-cell lymphoma.

Embodiment 63. The method of Embodiment 62, wherein the additionaltherapeutic agent is alemtuzumab, bendamustine, bexarotene, bleomycin,bortezomib, brentuximab vedotin, carboplatin, carfilzomib, carmustine,cisplatin, cyclophosphamide, cytarabine, dacarbazine, dazatinib,denileukin diftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate, prednisone,prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof.

Embodiment 64. A pharmaceutical composition for treating T-cell lymphomacomprising an ETP derivative, at least one additional therapeutic agentused in the treatment of T-cell lymphoma, and at least onepharmaceutically acceptable excipient.

Embodiment 65. The pharmaceutical composition of Embodiment 64, whereinthe ETP derivative is a compound having the structure of formula (1):

wherein:

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂, —SR^(1D),—SO_(n1)R^(1B), —SO_(v1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(2A), —NR^(2B)R^(2C), COOR^(2A), —CONR^(2B)R^(2C), —NO₂, —SR^(2D),—SO_(n2)R^(2B), —SO_(n2)OR^(2B), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(3A), —NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), NHC(O)NHNR^(3B)R^(3C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(4A), —NR^(4B)R^(4C), —COOR^(4A), —CONR^(4B)R^(4C), —NO₂, —SR^(4D),—SO_(n4)R^(4B), —SO_(n4)OR^(4B), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), NHC(O)NHNR^(4B)R^(4C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R⁵ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(5A), —NR^(5B)R^(5C), —COOR^(SA), —CONR^(5B)R^(5C), —NO₂, SR^(5D),SO_(n5)R^(5B), SO_(n5)OR^(5B), SO_(v5)NR^(5B)R^(5C), NHNR^(5B)R^(5C),ONR^(5B)R^(5C), NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(6A), —NR^(6B)R^(6C)—COOR^(6A), —CONR^(6B)R^(6C), —NO₂, SR^(6D),SO_(n6)R^(6B), SO_(n6)OR^(6B), SO_(v6)NR^(6B)R^(6C), NHNR^(6B)R^(6C),ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(16A), —NR^(16B)R^(16C), —COOR^(16A), —CONR^(16B)R^(16C), —NO₂,—SR^(16D), —SO_(n16)R^(16B), —SO_(n16)OR^(16B),—SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C), ONR^(16B)R^(16C),NHC(O)NHNR^(16B)R^(16C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(18A), —NR^(18B)R^(18C), —COOR^(18A), —CONR^(18B)R^(18C), —NO₂,—SR^(18D), —SO_(n18)R^(18B), —SO_(n18)OR^(18B),—SO_(v18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C), —OTR^(18B)R^(18C),—NHC(O)NHNR^(l8B)R^(18C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶, wherein R²⁸ and R²⁹ are optionally joinedto form *—S_(p)—* wherein p is an integer from 2 to 4 and each *represents the point of attachment to the remainder of the compound;

R²⁵ is hydrogen, —C(O)-L¹-R³², —C(S)-L¹-R³², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R²⁶ is hydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R²⁵ and R²⁶ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;

L² is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene;

R³² and R³³ are independently halogen, substituted or unsubstitutedC₁-C₃ alkyl, substituted or unsubstituted aryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B),R^(16C), R^(16D), R^(18A), R^(18B), R^(18C), and R^(18D) areindependently hydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

X is independently —F, —Cl, —Br, or —I;

n1, n2, n3, n4, n5, n6, n16, and n18 are independently an integer from 1to 4; and

v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2;

or a pharmaceutically acceptable salt thereof.

Embodiment 66. The pharmaceutical composition of Embodiments 64-65,wherein the additional therapeutic agent is alemtuzumab, bendamustine,bexarotene, bleomycin, bortezomib, brentuximab vedotin, carboplatin,carfilzomib, carmustine, cisplatin, cyclophosphamide, cytarabine,dacarbazine, dazatinib, denileukin diftitox, dexamethasone, doxorubicin,etoposide, everolimus, fludarabine, forodesine, gemcitabine,hydroxydaunorubicin, ifosfamide, imiquimod, interferons, lenalidomide,liposomal doxorubicin, mechlorethamine, methotrexate,methylprednisolone, nelfinavir, oral corticosteroids, panobinostat,pentostatin, pralatrexate, prednisone, prednisolone, psoralen,retinoids, resiquimod, rituximab, romidepsin, SGX301, temsirolimus,topical corticosteroids, vinblastine, vincristine, vinorelbine,vorinostat, or a combination thereof.

EXAMPLES Example 1

The compounds of Formulae I-XVIII can be prepared in a number of wayswell known to those skilled in the art, including both solid phase andsolution phase techniques. The compounds can be synthesized, forexample, by the methods described below, or variations thereof asappreciated by the skilled artisan. Although these syntheses areillustrated for preparation of ETPs having substituted aryl substituentsat C₆, identical sequences can be employed to prepare ETPs withsubstituted heteroaryl substituents at C₆. See e.g. Martins, M. M.;Carvalho Tetrahedron 2007, 63, 9923-9932; Borthwick, A. D. Chem Rev2012, 112, 3641-3716; Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr. J.Chem. 2011, 51, 420-433; Nicolaou, K. C.; Lu, M.; Totokotsopoulos, S.;Heretsch, P.; Giguère, D.; Sun, Y.-P.; Sarlah, D.; Nguyen, T. H.; Wolf,I. C.; Smee, D. F.; Day, C. W.; Bopp, S.; Winzeler, E. A. J. Am. Chem.Soc. 2012, 134, 17320-17332. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

Embodiments of Formula I may be prepared as shown in Scheme 1 above.Dehydrative condensation of an aldehyde with a glycine derivativerenders an intermediate imine such as 1, which when treated with base inthe presence of lithium bromide generates an azomethine ylide thatsubsequently undergoes a dipolar cycloaddition reaction to generate thedesired pyrrolidine product such as 2. The azomethine ylide can begenerated and the cycloaddition accomplished in many ways known in theart (Grigg, R. and V. Sridharan (1993). Azomethine Ylide Cycloadditionsvia 1,2-Prototropy and Metallo-Dipole Formation from Imines. Advances inCycloaddition. D. P. Curran. Greenwich, Conn., Jai Press Inc. 3:161-204). For example, the cycloaddition may be carried out by simplyheating the components in a solvent or by the use of other metalcomplexes or salts and other bases. Compounds 2 are typically generatedas mixtures of diasteroisomers, the isomer exemplified by 2 can beseparated from the mixture based on its reduced solubility in solventmixtures like MeOH/DCM (1:1). If required, the diastereoisomer productscan be obtained in high purity by column chromatography; the subsequentsteps can be performed with the separated stereoisomers or carried outwith the mixture of stereoisomers with separation being accomplished bycolumn chromatography, crystallization or other common techniques afterthe polysulfur bridge is incorporated.

The product of this cycloaddition reaction is a pyrrolidine ester, whichcan be converted to a dioxopiperazine in many well-known ways (Martins,M. B., Ivone, C. (2007) Diketopiperazines: biological activity andsynthesis. Tetrahedron 63, 9923-9932). For example, the pyrrolidineester can be acylated on the free nitrogen with an α-halo acid chlorideto yield the corresponding amide. These compounds can be treated with anexcess of a primary amine to undergo a cyclocondensation reactionfurnishing the desired diketopiperazine ring, compounds, exemplified by3 and 4. In general the diketopiperazine was isolated as mixture ofdiastereoisomers which need not be separated at this stage.Alternatively, the pyrrolidine ester can be coupled with an α-aminoester(typically protected on nitrogen) to give a dipeptide, which directly orupon removal of the nitrogen-protecting group can be cyclized to thedioxopiperazine intermediate.

The diketopiperazine then undergoes a sulfidation process, one exampleof which is illustrated in Scheme 1, to yield the desired ETP.Alternatively, the intermediate in this sequence, can be reduced and thedithiol product protected on the two sulfur atoms. The conversion of thediooxopiperazine intermediate to an ETP product can be accomplished inmany ways well known in the art (Iwasa, E.; Hamashima, Y.; Sodeoka, M.(2011) Epipolythiodiketopiperazine Alkaloids: Total Syntheses andBiological Activities Isr. J. Chem. 51, 420-433. Nicolaou, K. C., et al.(2011) Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-,and bis-(Methylthio)diketopiperazines: Synthetic Methodology,Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-RostratinB, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discoveryof New Antiviral and Antimalarial Agents J. Am. Chem. Soc., 133,8150-8153.)

Synthetic scheme for enantioselective synthesis of ETP analoguesdescribed herein.

To a stirred solution of racemic 1 (2.1 g, 7 mmol) in CH₂Cl₂ (14 mL)were added Et₃N (1.4 g, 14 mmol) and acyl chloride 2 (3.25 g, 10 mmol)in CH₂Cl₂ (14 mL) at 0° C. The reaction was stirred overnight. Thereaction was quenched with sat. NaHCO₃ and extracted with CH₂Cl₂. Thecombined organic layer was dried over MgSO₄ and evaporated to dryness.The crude product was purified by silica gel column chromatography byelution with 33% EtOAc/Hexane to afford 1.9 g (46%) of compound 3 and1.7 g (40%) of compound 4. For compound 3: ¹H NMR (400 MHz, CDCl₃) δ/ppm7.75 (d, 2H, J=7.4 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz),7.30 (t, 2H, J=7.4 Hz), 7.30 (s, 1H), 7.19 (dd, 1H, J=1.4, 8.0 Hz), 6.86(d, 2H, J=7.8 Hz), 6.00 (d, 2H, J=6.6 Hz), 5.22 (s, 1H), 5.19 (d, 2H,J=7.8 Hz), 4.60 (dd, 1H, J=7.4, 9.8 Hz), 4.39-4.22 (m, 4H), 4.20-4.14(m, 2H), 2.59 (dd, 1H, J=9.8, 13.8 Hz), 2.35 (dd, 1H, J=7.0, 13.8 Hz),1.61 (s, 3H), 1.35 (t, 3H, J=7.0 Hz), 0.98 (d, 3H, J=7.0 Hz); ¹³C NMR(100 MHz, CDCl₃) δ/ppm 174.0, 170.2, 156.1, 148.31, 148.27, 143.70,143.65, 141.3, 131.8, 127.75, 127.72, 127.0, 125.1, 125.0, 121.3, 120.0,108.6, 107.8, 101.4, 70.3, 67.2, 61.9, 58.2, 47.8, 47.0, 44.5, 37.3,24.3, 17.4, 14.1;

For compound 4 (main rotamer): ¹H NMR (400 MHz, CDCl₃) δ/ppm 7.75 (d,2H, J=7.4 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.30 (t,2H, J=7.4 Hz), 7.30 (s, 1H), 7.19 (dd, 1H, J=1.4, 8.0 Hz), 7.03 (s, 1H),6.93 (d, 1H, J=7.8 Hz), 6.80 (d, 1H, J=8.2 Hz), 5.95 (d, 2H, J=2.2 Hz),5.37 (dd, 1H, J=3.4, 8.2 Hz), 5.27 (d, 1H, J=7.6 Hz), 4.76 (s, 1H),4.40-4.10 (m, 6H), 2.90 (dd, 1H, J=3.4, 13.2 Hz), 2.41 (dd, 1H, J=2.3,13.2 Hz), 1.62 (s, 3H), 1.40 (d, 3H, J=7.0 Hz), 1.39 (t, 3H, J=7.0 Hz);¹³C NMR (100 MHz, CDCl₃) δ/ppm 174.0, 170.9, 156.3, 147.9, 147.7,143.64, 143.62, 141.3, 130.6, 127.8, 127.7, 127.0, 125.1, 125.0, 120.2,120.0, 108.3, 107.0, 101.1, 70.8, 67.2, 62.6, 59.3, 48.4, 47.0, 43.4,40.8, 23.1, 17.8, 14.1;

To a stirred solution of compound 3 (2.8 g, 4.7 mmol) in CH₂Cl₂ (18 mL)was added piperidine (4.0 g, 47 mmol). After 30 min, the solvent wasremoved. The crude product was purified by silica gel columnchromatography by elution with 3% MeOH/CH₂Cl₂ to afford 1.4 g (91%) ofcompound 5 as white solid. ¹H NMR (400 MHz, CDCl₃) δ/ppm 6.79 (d, 2H,J=7.8 Hz), 6.63 (dd, 1H, J=2.0, 8.2 Hz), 6.57 (d, 2H, J=2.0 Hz), 5.96(s, 2H), 5.91 (s, 1H), 4.87 (s, 1H), 4.43 (dd, 1H, J=6.6, 11.0 Hz), 4.17(q, 1H, J=6.6 Hz), 2.82 (dd, 1H, J=11.4, 13.4 Hz), 2.35 (dd, 1H, J=6.6,13.4 Hz), 1.68 (s, 3H), 1.44 (d, 3H, J=6.6 Hz); ¹³C NMR (100 MHz, CDCl₃)δ/ppm 168.9, 166.9, 148.3, 148.2, 130.8, 119.7, 108.7, 106.2, 101.4,69.3, 57.5, 51.6, 42.8, 35.8, 25.3, 15.4;

To a stirred solution of compound 5 (1.4 g, 4.3 mmol) in THF (43 mL) wasadded NaH (60%, 260 mg, 6.5 mmol) at 0° C. After 20 min at 23° C., Mel(1.85 g, 13 mmol) was added at 0° C. After 2 h at 23° C., the reactionwas quenched with sat. NH4Cl. The solvent was removed and the residuewas extracted with CH₂Cl₂. The combined organic layer was dried overMgSO₄ and evaporated to dryness. The crude product was purified bysilica gel column chromatography by elution with 25% EtOAc/Hexane toafford 1.25 g (86%) of compound 6. ¹H NMR (400 MHz, CDCl₃) δ/ppm 6.82(d, 2H, J=8.2 Hz), 6.73 (d, 1H, J=2.0 Hz), 6.71 (s, 1H), 5.98 (s, 2H),4.73 (dd, 1H, J=6.2, 10.6 Hz), 3.88 (q, 1H, J=7.0 Hz), 3.01 (s, 3H),2.93 (dd, 1H, J=6.2, 13.0 Hz), 2.26 (dd, 1H, J=10.6, 13.0 Hz), 1.60 (s,3H), 1.54 (d, 3H, J=7.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ/ppm 165.9,165.2, 148.2, 148.1, 129.3, 120.3, 119.4, 108.6, 106.1, 101.4, 70.2,60.6, 58.4, 44.1, 41.6, 32.1, 22.7, 16.7;

To a suspension of elemental sulfur (300 mg, 9.4 mmol) in dry THF (10mL) NaHMDS (0.6 M in toluene, 7.40 mL) is being added dropwise. Theresulting yellow reaction mixture is stirred at ambient temperature forone minute and then combined with a slurry of the substrate 6 (340 mg,1.0 mmol in 5 mL dry THF). A second portion of NaHMDS (0.6 M in toluene,4.8 mL) is subsequently added resulting in an orange mixture which isstirred at ambient temperature for 30 minutes. After quenching withsaturated aqueous ammonium chloride, the solvent was removed and theresidue was extracted with CH₂Cl₂. The combined organic layer was driedover MgSO₄ and evaporated to dryness. The crude product was purified bysilica gel column chromatography by elution with 2% EtOAc/CH₂Cl₂ toafford 129 mg (32%) of compound 7. ¹H-NMR (400 MHz, CDCl₃): δ/ppm 6.96(s, 1H), 6.91 (s, 2H), 6.06 (s, 2H), 4.89 (s, 1H), 3.36 (d, 1H, J=14.5Hz), 3.14 (s, 3H), 3.06 (d, 1H, J=14.5 Hz), 2.00 (s, 3H), 1.73 (s, 3H);¹³C-NMR (100 MHz, CDCl₃): δ/ppm 165.6, 162.1, 148.6, 148.3, 127.5,120.7, 120.3, 108.6, 107.2, 101.6, 73.4, 73.3, 72.4, 44.4, 42.8, 27.8,24.8, 18.1. ^(α)[D]₂₀=+240°, ee %>99%

See procedure as preparing compound 5. ¹H NMR (400 MHz, DMSO-d₆) δ/ppm8.45 (d, 1H, J=4.2 Hz), 6.88 (d, 1H, J=8.2 Hz), 6.70 (s, 1H), 6.60 (d,1H, J=7.4 Hz), 6.00 (s, 2H), 4.87 (s, 1H), 4.73 (dd, 1H, J=6.6, 11.0Hz), 3.78-3.70 (m, 1H), 2.42-2.26 (m, 2H), 1.62 (s, 3H), 1.35 (d, 3H,J=7.4 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ/ppm 168.6, 167.6, 147.7, 147.4,133.2, 121.4, 119.8, 108.6, 107.1, 101.7, 68.3, 55.8, 53.5, 42.6, 36.1,24.4, 18.8;

See procedure as preparing compound 6. ¹H-NMR (400 MHz, CDCl₃): δ/ppm6.79 (d, 1H, J=9.0 Hz), 6.63 (d, 1H, J=9.0 Hz), 6.57 (s, 1H), 5.96 (s,2H), 4.82 (s, 1H), 4.36 (dd, 1H, J=6.5, 11.0 Hz), 3.90 (q, 1H, J=7.0Hz), 3.04 (s, 3H), 2.76 (t, 1H, J=7.0 Hz), 2.45 (dd, 1H, J=6.5, 13.5Hz), 1.66 (s, 3H), 1.47 (d, 3H, J=7.0 Hz); ¹³C-NMR (100 MHz, CDCl₃):δ/ppm 166.6, 166.0, 148.2, 148.1, 130.8, 119.9, 119.8, 108.6, 106.2,101.4, 69.6, 60.8, 56.1, 42.6, 36.7, 32.0, 25.1, 15.3;

See procedure as preparing compound 7. ¹H-NMR (400 MHz, CDCl₃): δ/ppm6.96 (s, 1H), 6.91 (s, 2H), 6.06 (s, 2H), 4.89 (s, 1H), 3.36 (d, 1H,J=14.5 Hz), 3.14 (s, 3H), 3.06 (d, 1H, J=14.5 Hz), 2.00 (s, 3H), 1.73(s, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ/ppm 165.6, 162.1, 148.6, 148.3,127.5, 120.7, 120.3, 108.6, 107.2, 101.6, 73.4, 73.3, 72.4, 44.4, 42.8,27.8, 24.8, 18.1. ^(α)[D]₂₀=−216°, ee %>95%.

Example 2

General Procedure for the Synthesis of Polyfunctionalized PyrrolidineEsters.

Dimethylrac-(2S,4S,5S)-5-(4-Fluorophenyl)-4-methylpyrrolidine-2,4-dicarboxylate

4-Fluorobenzaldehyde (1.24 g, 10 mmol) was dissolved in 15 mL of MeCNcontaining triethylamine (1.5 mL, 11 mmol) and glycine methyl esterhydrochloride (1.35 g, 11 mmol). The reaction mixture was stirred for 5h at room temperature. After removing the solvent in vacuo, the solidresidue was re-dissolved in CH₂Cl₂ and washed twice from water to givethe imine intermediate as colourless oil. To a solution of this materialin 20 mL of THF, solid LiBr (1.1 g, 12 mmol) and triethylamine (1.7 mL,12 mmol) were added portionwise. After 2 min, methyl methacrylate (1.5g, 15 mmol) was added and the resulting solution was stirred at roomtemperature for 8 h. After evaporation of the solvent in vacuo andextractive work-up (3 times, CH₂Cl₂/water), the desired product wasisolated as yellow oil (2.6 g, 90% yield, as a single diastereomer). Insome cases the cycloadduct was isolated as a mixture of C4 epimers,which were separated by crystallization or chromatography

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.30 (2H, m), 7.03 (2H, t, J=8.5 Hz),4.09 (1H, s), 4.06 (1H, t, J=7.0 Hz), 3.86 (3H, s), 3.30 (3H, s), 2.95(1H, br. s, NH), 2.76 (1H, dd, J=7.0, 13.5 Hz), 2.14 (1H, dd, J=13.0,13.5 Hz), 1.43 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 174.6 (C), 174.3(C), 162.3 (C, J_(C-F)=245 Hz), 134.7 (C, J_(C-F)=3 Hz), 128.4 (2CH, d,J_(C-F)=8 Hz), 115.0 (2CH, d, J_(C-F)=21 Hz), 73.1 (CH), 58.8 (CH), 54.6(C), 52.3 (CH₃), 51.5 (CH₃), 41.1 (CH₂), 22.5 (CH₃). LR-MS: 295.96;HR-MS (ESI) calculated for C₁₅H₁₈NO₄FCl: 296.1298 (M+H⁺), found:296.1302.

2-Ethyl rac-4-Methyl(2S,4S,5S)-4-methyl-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate

Isolated as pale yellow oil, dr (diastereomer ratio)>9:1. ¹H-NMR (500MHz, CDCl₃): δ/ppm 8.26 (1H, s), 8.23 (1H, dd, J=1.5, 4.5 Hz), 7.45 (1H,dd, J=1.5, 8.0 Hz), 6.98 (1H, dd, J=4.5, 9.0 Hz), 4.00-4.12 (2H, m),3.85 (2H, s), 3.78 (1H, app. t, J=7.5 Hz), 2.99 (3H, s), 2.48 (1H, dd,J=8.0, 13.0 Hz), 1.86 (1H, dd, J=8.0, 13.0 Hz), 1.17 (3H, s), 1.07 (3H,t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 173.9 (C), 173.3 (C),148.9 (CH), 148.6 (CH), 134.9 (C), 133.9 (CH), 122.8 (CH), 70.7 (CH),60.8 (CH₂), 58.5 (CH), 54.4 (C), 51.1 (CH₃), 40.3 (CH₂), 22.4 (CH₃),14.0 (CH₃). IR (film): v/cm⁻¹ 3380, 2981, 2950, 1732, 1430, 1210, 1110,1029, 716. LR-MS: 293.1 (M+H⁺); HR-MS (ESI) calculated for C₁₅H₂₀N₂O₄Na:315.1321 (M+Na⁺), found: 315.1315.

2-Ethyl 4-Methylrac-(2S,4S,5S)-5-(5-Bromo-2-methoxyphenyl)-4-methylpyrrolidine-2,4-dicarboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.45 (1H, d, J=2.5 Hz), 7.28 (1H, dd, J=2.5, 9.0 Hz), 6.70 (1H, d,J=9.0 Hz), 4.45 (1H, s), 4.25 (2H, q, J=7.0 Hz), 3.96 (1H, app. t, J=8.0Hz), 3.74 (3H, s), 3.30 (3H, s), 2.72 (1H, dd, J=9.0, 13.0 Hz), 2.05(1H, dd, J=9.0, 13.0 Hz), 1.36 (3H, s), 1.24 (3H, t, J=7.0 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 174.7 (C), 173.4 (C), 156.3 (C), 131.1 (CH),130.4 (CH), 129.4 (C), 112.7 (C), 112.0 (CH), 66.8 (CH), 61.0 (CH₂),59.0 (CH₃), 55.4 (CH₃), 54.5 (C), 51.3 (CH), 41.7 (CH₂), 22.8 (CH₃),14.2 (CH₃). IR (film): v/cm⁻¹ 3366, 2980, 2938, 2839, 2236, 1736, 1486,1252, 1202, 1134, 1028, 809. LR-MS: 389.0 (M+Na⁺); HR-MS (ESI)calculated for C₁₆H₁₉N₂O₃BrNa: 389.0477 (M+Na⁺), found: 389.0471.

4-(tert-Butyl) 2-Ethylrac-(2S,4S,5S)-5-(4-Fluorophenyl)-4-methylpyrrolidine-2,4-dicarboxylate

Isolated as yellow oil (dr>9:1). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.37(2H, dd,J=5.5, 8.0 Hz), 7.04 (2H, app. t, J=8.0 Hz), 4.31 (2H, q, J=7.0Hz), 4.08 (1H, s), 4.03 (1H, t, J=8.5 Hz), 2.69 (1H, br. s), 2.66 (1H,dd, J=9.0, 13.0 Hz), 2.12 (1H, dd, J=8.5, 13.0 Hz), 1.49 (3H, s), 1.36(3H, t, J=7.0 Hz), 1.13 (9H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 173.7(C), 173.4 (C), 162.3 (C, d, J=244 Hz), 135.9 (C), 128.9 (2CH, d, J=8Hz), 114.9 (2CH, d, J=21 Hz), 80.8 (C), 72.3 (CH), 61.2 (CH₂), 58.9(CH), 55.1 (C), 41.9 (CH₂), 27.6 (3CH₃), 24.3 (CH₃), 14.3 (CH₃). IR(film): v/cm⁻¹ 3368, 2979, 2935, 1724, 1511, 1369, 1224, 1154. LR-MS:352.2 M+H⁺; HR-MS (ESI) calculated for C₁₉H₂₆NO₄FNa: 374.1743 (M+Na⁺),found: 374.1742.

Ethyl rac-(2S,4S,5S)-4-Cyano-4-methyl-5-phenylpyrrolidine-2-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52 (2H, d, J=7.1 Hz), 7.41-7.34 (3H,m), 4.34-4.24 (2H, m), 3.98 (1H, dd, J=4.2, 9.7 Hz), 3.93 (1H, s), 2.90(1H, s), 2.82 (1H, dd, J=4.2, 13.6 Hz), 2.29 (1H, dd, J=9.6, 13.6 Hz),1.42 (3H, s), 1.34 (3H, t, J=7.1 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm173.0 (C), 136.5 (C), 128.9 (CH), 128.6 (2CH), 127.6 (2CH), 121.9 (C),72.4 (CH), 61.7 (CH₂), 57.3 (CH), 44.1 (C), 42.5 (CH₂), 22.0 (CH₃), 14.2(CH₃); IR (film): v/cm−¹ 3348, 2980, 2234, 1734, 1454; LR-MS: 281.1[M+Na]⁺; HR-MS (ESI) calculated for C₁₅H₁₈N₂O₂Na: 281.1266, found:281.1263.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(4-fluorophenyl)-4-methylpyrrolidine-2-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52 (2H, dd, J=5.4, 8.7 Hz), 7.09 (2H,t, J=8.7 Hz), 4.34-4.24 (2H, m), 4.00 (1H, dd, J=4.2, 9.6 Hz), 3.95 (1H,s), 2.83 (1H, dd, J=4.2, 13.7 Hz), 2.82 (1H, s), 2.30 (1H, dd, J=9.6,13.7 Hz), 1.41 (3H, s), 1.34 (3H, t, J=7.1 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 172.9 (C), 163.2 (C, d, J=246 Hz), 132.4 (C), 129.4 (2CH,d, J=8 Hz), 121.8 (C), 115.7 (2CH, d, J=22 Hz), 71.7 (CH), 61.9 (CH₂),57.3 (CH), 44.0 (C), 42.2 (CH₂), 22.0 (CH₃), 14.3 (CH₃); IR (film):v/cm⁻¹ 3348, 2982, 2235, 1736, 1605, 1510; LR-MS: 299.1 [M+Na]⁺; HR-MS(ESI) calculated for C₅H₁₇FN₂O₂Na: 299.1172, found: 299.1177.

Ethylrac-(2S,4S,5S)-5-(Benzo[d][1,3]dioxol-5-yl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (dr=3:2). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.12 (1H,s), 6.98 (1H, d, J=8.5 Hz), 6.83 (1H, d, J=8.5 Hz), 5.99 (2H, s), 4.31(2H, q, J=7.0 Hz), 3.98 (1H, dd, J=4.5, 9.5 Hz), 3.89 (1H, s), 2.83 (1H,dd, J=4.0, 13.5 Hz), 2.75 (1H, br. s), 2.29 (1H, dd, J=9.5, 13.5 Hz),1.44 (3H, s), 1.36 (3H, t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm173.0 (C), 148.0 (C), 147.9 (C), 130.6 (C), 122.1 (C), 121.1 (CH), 108.2(CH), 107.9 (CH), 101.3 (CH₂), 72.1 (CH), 61.6 (CH₂), 57.0 (CH), 43.8(C), 42.1 (CH₂), 22.1 (CH₃), 14.2 (CH₃). IR (film): v/cm⁻¹3361, 2984,2900, 2254, 1734, 1490, 1447, 1265, 1041, 909. LR-MS: 325.1 M+Na⁺; HR-MS(ESI) calculated for C₁₆H₁₈N₂O₄Na: 325.1164 (M+Na⁺), found: 325.1161.

Ethylrac-(2S,4S,5R)-5-(6-Bromobenzo[d][1,3]dioxol-5-yl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.48 (1H, s), 6.96 (1H, s), 5.97 (1H, s), 5.92 (1H, s), 4.56 (1H,s), 4.20 (2H, q, J=7.0 Hz), 4.00 (1H, m), 2.67 (1H, dd, J=6.0, 8.0 Hz),2.65 (1H, broad s), 2.27 (1H, dd, J=9.0, 13.5 Hz), 1.53 (3H, s), 1.27(3H, t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.8 (C), 148.3 (C),147.6 (C), 130.9 (C), 122.0 (C), 114.5 (C), 112.4 (CH), 109.4 (CH),102.0 (CH₂), 68.5 (CH), 61.4 (CH₂), 57.1 (CH), 44.3 (C), 41.4 (CH₂),23.3 (CH₃), 14.2 (CH₃). IR (film): v/cm⁻¹ 3366, 2981, 2904, 2237, 1737,1504, 1477, 1408, 1241, 1205, 1117, 1037, 931, 846. LR-MS: 381.2 M+Na⁺.

Ethylrac-(2S,4S,5R)-5-(5-Bromo-2-methoxyphenyl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.89 (1H, d, J=2.5 Hz), 7.37 (1H, dd, J=2.5, 9.0 Hz), 6.77 (1H, d,J=9.0 Hz), 4.47 (1H, s), 4.27 (2H, q, J=7.5 Hz), 3.98 (1H, t, J=7.5 Hz),3.83 (3H, s), 2.71 (1H, br s), 2.62 (1H, dd,J=7.0, 13.0 Hz), 2.26 (1H,dd, J=8.5, 13.0 Hz), 1.49 (3H, s), 1.34 (3H, t, J=7.5 Hz); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 172.7 (C), 156.4 (C), 131.9 (CH), 131.1 (CH), 129.1(C), 122.3 (C), 113.1 (C), 112.2 (CH), 64.5 (CH), 61.5 (CH₂), 57.7 (CH),55.5 (CH₃), 43.9 (C), 41.8 (CH₂), 23.6 (CH₃), 14.3 (CH₃). IR (film):v/cm⁻¹ 3366, 2980, 2938, 2904, 2839, 2236, 1736, 1486, 1463, 1252, 1202,1134, 1028, 809. LR-MS: 389.0 M+Na⁺; HR-MS (ESI) calculated forC₁₆H₁₉N₂O₃Na: 389.0477, found: 389.0471.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=4:1). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.38(1H, s), 7.22 (1H, d, J=8.5 Hz), 7.06 (1H, d, J=8.5 Hz), 4.24-4.34 (2H,m), 3.97 (11, s), 3.95-4.01 (1H, m), 2.84 (1H, dd, J=4.5, 9.0 Hz), 2.68(1H, s), 2.29 (1H, dd, J=4.5, 8.5 Hz), 1.44 (3H, s), 1.33 (3H, t, J=9.0Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.7 (C), 144.1 (C), 133.7 (C),133.3 (C), 131.8 (C, t, J=250 Hz), 123.1 (CH), 121.6 (C), 109.3 (CH),109.1 (CH), 71.9 (CH), 61.8 (CH₂), 57.0 (CH), 43.9 (C), 41.8 (CH₂), 22.1(CH₃), 14.2 (CH₃). IR (film): v/cm⁻¹ 3351, 3078, 2983, 2236, 1738, 1497,1448, 1382, 1239, 1148, 1034, 818, 703.

Ethylrac-(2S,4S,5S)-5-(3,4-Bis(allyloxy)phenyl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=4:1). ¹H-NMR (500 MHz, CDCl₃) δ/ppm 7.17 (d,J=1.5 Hz, 1H), 7.01-6.99 (m, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.13-6.04 (m,2H), 5.47-5.40 (m, 2H), 5.31-5.26 (m, 2H), 4.66-4.60 (m, 4H), 4.33-4.26(m, 2H), 3.96 (dd, J=9.6, 3.9 Hz, 1H), 3.85 (s, 1H), 2.82 (dd, J=13.6,4.1 Hz, 1H), 2.75 (broads, 1H), 2.27 (dd, J=13.6, 9.7 Hz, 1H), 1.40 (s,3H), 1.33 (t, J=7.6 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ/ppm 173.2(C), 149.1 (C), 148.6 (C), 133.5 (2×CH), 129.4 (C), 122.2 (C), 120.5(CH), 118.0 (CH₂), 117.8 (CH₂), 113.8 (CH), 113.4 (CH), 72.4 (CH), 70.2(CH₂), 70.0 (CH₂), 61.8 (CH₂), 57.3 (CH), 44.0 (C), 42.5 (C₂), 22.1(CH₃), 14.3 (C₃) ppm; IR (film) v/cm⁻¹ 2982, 2936, 1735, 1649, 1513,1454, 1426, 1378, 1265, 1217, 1138, 1021, 997, 929, 810 cm⁻¹; HRMS (ESI)calcd for C₂₁H₂₆N₂O₄Na⁺ (M+Na) 393.1790, found 393.1796.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(7-methoxybenzo[d][1,3]dioxol-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=3:2). ¹H-NMR (500 MHz, CDCl₃) δ/ppm 6.78 (s,1H), 6.67 (s, 1H), 5.96 (s, 2H), 4.29-4.22 (m, 2H), 3.93 (dd, J=9.5, 4.3Hz, 1H), 3.91 (s, 3H), 3.82 (s, 1H), 2.78 (dd, J=13.6, 4.3 Hz, 1H), 2.68(broad s, 1H), 2.24 (dd, J=13.6, 9.6 Hz, 1H), 1.40 (s, 3H), 1.31 (t,J=7.2 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ/ppm 172.9 (C), 148.8 (C),143.6 (C), 135.6 (C), 131.4 (C), 122.0 (C), 107.1 (CH), 101.9 (CH),101.7 (CH₂), 72.3 (CH), 61.7 (CH₂), 57.1 (CH₃), 56.7 (CH), 43.9 (C),42.1 (CH₂), 22.2 (CH₃), 14.2 (CH₃) ppm; IR (film) v/cm⁻¹ 2979, 2235,1735, 1635, 1510, 1452, 1381, 1323, 1291, 1202, 1138, 1094, 1043, 929,855, 831, 733 cm⁻¹; HRMS (ESI) calcd for C₁₇H₂₀N₂O₅Na⁺ (M+Na) 355.1270,found 355.1261.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(2,3-dihydro-1H-inden-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=1:1). ¹H-NMR (500 MHz, CDCl₃) δ 7.40 (s, 1H),7.27-7.23 (m, 2H), 4.34-4.26 (m, 2H), 3.98 (dd, J=9.6, 3.9 Hz, 1H), 3.90(s, 1H), 2.97-2.89 (m, 4H), 2.83 (dd, J=13.8, 4.2 Hz, 1H), 2.30 (dd,J=13.8, 9.7 Hz, 1H), 2.09 (app. quintet, J=7.4 Hz, 2H), 1.62 (broad s,1H), 1.42 (s, 3H), 1.35 (t, J=7.3 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 173.2 (C), 145.3 (C), 144.8 (C), 134.3 (C), 125.6 (CH), 124.5 (CH),123.4 (CH), 122.2 (C), 72.8 (CH), 61.8 (CH₂), 57.5 (CH), 44.2 (C), 42.8(CH₂), 33.0 (CH₂), 32.8 (CH₂), 25.6 (CH₂), 22.1 (CH₃), 14.4 (CH₃) ppm;IR (film) v/cm⁻¹ 2940, 2234, 1735, 1447, 1378, 1209, 1139, 1097, 1032,826 cm⁻¹; HRMS (ESI) calcd for CH₂₂N₂O₂Na⁺ (M+Na) 321.1579, found321.1577.

Ethylrac-(2S,4S,5S)-4-Cyano-4-methyl-5-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrrolidine-2-carboxylate

Isolated as a yellow, highly viscous oil. ¹H-NMR (500 MHz, CDCl₃) δ 7.98(d, J=6.4 Hz, 2H), 7.93 (d, J=8.3 Hz, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.52(t, J=7.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.32 (t, J=7.7 Hz, 1H), 7.23(t, J=7.6 Hz, 1H), 4.35-4.28 (m, 2H), 4.27 (d, J=5.6 Hz, 1H), 4.04-4.00(m, 1H), 2.88 (dd, J=13.7, 4.3 Hz, 1H), 2.81 (broad s, 1H), 2.33 (dd,J=13.7, 9.8 Hz, 1H), 1.46 (s, 3H), 1.37 (t, J=7.1 Hz, 3H) ppm; ¹³C-NMR(126 MHz, CDCl₃) δ 172.7 (C), 137.9 (C), 135.1 (C), 134.0 (CH), 129.8(C), 129.4 (CH), 127.2 (CH), 125.2 (CH), 125.1 (CH), 123.4 (CH), 122.2(C), 119.8 (CH), 119.1 (C), 113.9 (CH), 64.6 (CH), 61.9 (CH₂), 57.4(CH), 44.6 (C), 42.6 (CH₂), 22.4 (CH₃), 14.3 (CH₃) ppm; IR (film) v/cm⁻¹2980, 2235, 1735, 1606, 1447, 1369, 1273, 1212, 1176, 1125, 1092, 1024,979, 858, 750, 722 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₃N₃O₄SNa⁺ (M+Na)460.1307, found 460.1305.

Example 3

General Procedure for Forming Diketopiperazines by Sequential Reactionof Pyrrolidine Esters with 2-Chloroalkanonyl Chlorides and Amines.

Methylrac-(3R,6S,7S,8aS)-6-(4-Fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The corresponding pyrrolidine (1.0 equiv) was dissolved in 10 mL ofCH₂Cl₂ and cooled to 0° C. with an ice-bath. Triethylamine (1.2 equiv)was added, followed by dropwise addition of a solution of2-chloropropionyl chloride (1.2 equiv, 50% v/v in CH₂Cl₂). This mixturewas stirred for 1 h with cooling, followed by 1 h after removal of theice-bath. The intermediate α-chloroamide is then directly extracted(3×CH₂Cl₂) and isolated as brownish foam after removal of the volatilesin vacuo. The corresponding amide was re-dissolved in 10 mL of CH₂Cl₂and combined with the equivalent volume of 40% aq MeNH₂ solution to givea biphasic mixture, which was stirred at rt for 12-16 h. Extraction ofthis mixture gives the crude diketopiperazine (DKP) product as yellowfoam (purity 50-80%). This residue was stirred with MeOH (1 M) for 1 h,whereupon a colorless solid was obtained 70% yield. Trituration of thismaterial from a methanolic solution in CH₂Cl₂ (often accelerated byvigorous stirring) gave the major DKP stereoisomer as a colorless solidafter filtration and drying under high vacuum. Either the pure DKPsteroisomer, or the solid 5:1 mixture of DKP isomers, could be employedin the subsequent sulfidation step.

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.00-7.10 (2H, m), 6.91 (2H, t, J=8.5Hz), 4.81 (1H, s), 4.36 (1H, dd, J=6.5, 11.5 Hz), 3.81 (1H, q, J=9.0Hz), 3.22 (3H, s), 2.94 (3H, s), 2.90-2.95 (1H, m), 2.16 (1H, dd, J=6.5,14.0 Hz), 1.53 (3H, s), 1.44 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 172.1 (C), 167.3 (C), 166.9 (C), 162.3 (C, d, J=249 Hz),133.6 (C, d, J=3 Hz), 128.3 (2 CH, d, J=8 Hz), 115.2 (2 CH, d, J=21 Hz),69.4 (CH), 60.9 (CH), 56.9 (CH), 53.3 (C), 51.9 (CH₃), 34.4 (CH₂), 32.0(CH₃), 24.2 (CH₃), 15.3 (CH₃). IR (film): v/cm⁻⁴ 2975, 2929, 1736, 1677,1605, 1509, 1433, 1401, 1299, 1248, 1225, 1126, 1158, 849. LR-MS: 371.07(M+Na⁺); HR-MS (ESI) calculated for C₁₈H₂₂N₂O₄F: 349.1564 (M+H⁺), found:349.1570.

tert-Butylrac-(3R,6S,7S,8aS)-6-(4-Fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.06-7.13 (2H, m), 6.91-6.95 (2H, m),4.76 (1H, s), 4.34 (1H, dd, J=7.0, 12.0 Hz), 3.79 (1H, q, J=7.0 Hz),3.00 (3H, s), 2.92-3.00 (1H, m), 2.17 (1H, dd, J=6.5, 14.0 Hz), 1.51(3H, s), 1.45 (3H, d, J=7.0 Hz), 1.05 (9H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 170.8 (C), 167.3 (C), 166.7 (C), 162.3 (C, d, J=250 Hz), 134.2(C), 129.2 (2CH), 115.1 (2CH, d, J=21 Hz), 81.4 (C), 69.3 (CH), 60.8(CH), 56.7 (CH), 53.4 (C), 34.8 (CH₂), 31.9 (CH₃), 27.3 (3CH₃), 25.2(CH₃), 15.2 (CH₃). IR (film): v/cm⁻¹ 2977, 2934, 1724, 1673, 1510, 1452,1430, 1401, 1369, 1304, 1250, 1228, 1167, 1124, 848, 734. LR-MS: 413.2(M+Na⁺); HR-MS (ESI) calculated for C₂₁H₂₇N₂O₄FNa: 413.1852 (M+Na⁺),found: 413.1846.

Methylrac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo-[1,2-a]pyrazine-7-carboxylate

Isolated as an 8:1 mixture of diastereomers, data for the major isomeris reported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.68 (1H, d, J=8.0 Hz), 6.54(1H, d, J=8.0 Hz), 6.51 (1H, s), 5.90 (2H, s), 4.78 (1H), 4.36 (1H, dd,J=6.5, 11.5 Hz), 3.85 (1H, app. t, J=7.0 Hz), 3.32 (3H, s), 3.03 (3H,s), 2.90-3.00 (1H, m), 2.16 (1H, dd, J=6.5, 8.5 Hz), 1.53 (3H, s), 1.41(3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.09 (C), 167.2 (C), 166.8(C), 147.5 (C), 147.3 (C), 131.4 (C), 120.3 (CH), 108.0 (CH), 106.9(CH), 101.1 (CH₂), 69.8 (CH), 60.8 (CH), 56.8 (CH₃), 53.2 (C), 51.9(CH), 34.2 (CH₂), 32.0 (CH₃), 24.1 (CH₃), 15.2 (CH₃). LR-MS: 416.1M+Na⁺; IR (film): v/cm⁻¹ 2953, 2949, 1735, 1672, 1490, 1432, 1294, 1245,1122, 1037. HR-MS (ESI) calculated for C₁₉H₂₂N₂O₆Na: 397.1375 (M+Na⁺),found: 397.1367.

Rac-(3R,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-phenyloctahydropyrrolo-[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (600 MHz, CDCl₃): δ/ppm 7.39-7.33 (3H, m), 7.12 (2H, d, J=7.2Hz), 4.91 (1H, s), 4.40 (1H, dd, J=6.6, 11.4 Hz), 3.91 (1H, q, J=3.6,7.2 Hz), 3.05 (3H, s), 2.79 (1H, t, J=11.4 Hz), 2.46 (1H, dd, J=6.6,13.2 Hz), 1.69 (3H, s), 1.48 (3H, d, J=7.2 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.7 (C), 166.2 (C), 136.9 (C), 129.2 (2CH), 129.1 (2CH),126.1 (CH), 119.9 (C), 69.8 (CH), 60.9 (CH), 56.3 (CH), 42.6 (C), 36.7(CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃); IR (film): v/cm⁻¹ 2981, 2937,2244, 1673; LR-MS: 320.1 [M+Na]⁺; HR-MS (ESI) calculated forC₁₇H₁₉N₃O₂Na: 320.1375, found: 320.1380.

Rac-(3R,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo-[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.13-7.05 (4H, m), 4.90 (1H, s), 4.39(1H, dd, J=6.5, 11.0 Hz), 3.90 (1H, q, J=7.0 Hz), 3.06 (3H, s), 2.76(1H, t, J=12.0 Hz), 2.47 (1H, dd, J=6.5, 13.5 Hz), 1.69 (3H, s), 1.49(3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.8 (C), 166.1 (C),163.0 (C, d, J=247 Hz), 132.8 (C, d, J=3 Hz), 127.9 (2CH, d, J=8 Hz),119.8 (C), 116.2 (2CH, d, J=22 Hz), 69.2 (CH), 60.9 (CH), 56.3 (CH),42.6 (C), 36.8 (CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃); IR (film):v/cm⁻¹ 2989, 2940, 2241, 1681; LR-MS: 338.1 [M+Na]⁺; HR-MS (ESI)calculated for C₁₇H₁₈FN₃O₂Na: 338.1281, found: 338.1283.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]-pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.79 (1H, d, J=9.0 Hz), 6.63 (1H, d,J=9.0 Hz), 6.57 (1H, s), 5.96 (2H, s), 4.82 (1H, s), 4.36 (1H, dd,J=6.5, 11.0 Hz), 3.90 (1H, app q, J=7.0 Hz), 3.04 (3H, s), 2.76 (1H, appt, J=7.0 Hz), 2.45 (1H, dd, J=6.5, 13.5 Hz), 1.66 (3H, s), 1.47 (3H, d,J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.6 (C), 166.0 (C), 148.2(C), 148.1 (C), 130.8 (C), 119.9 (CH), 119.8 (C), 108.6 (CH), 106.2(CH), 101.4 (CH₂), 69.6 (CH), 60.8 (CH), 56.1 (CH), 42.6 (C), 36.7(CH₂), 32.0 (CH₃), 25.1 (CH₃), 15.3 (CH₃). LR-MS: 364.0 M+Na⁺; IR (film)v/cm⁻¹: 2982, 2917, 2244, 1671, 1491, 1447, 1246, 1037, 925, 721 v/cm⁻¹.HR-MS (ESI) calculated for C₁₈H₁₉N₃O₄Na: 364.1273 (M+Na⁺), found:364.1273.

Rac-(6R,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(thiophen-2-yl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.31 (1H, m), 7.11 (1H, s), 7.06 (1H, m),5.27 (1H, s), 4.39 (1H, dd, J=6.5, 11.0 Hz), 3.95 (1H, q, J=7.5 Hz),3.08 (3H, s), 3.00 (1H, app t, J=13.0 Hz), 2.56 (1H, dd, J=6.5, 13.0Hz), 1.72 (3H, s), 1.52 (3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 166.9 (C), 166.0 (C), 140.4 (C), 127.5 (CH), 127.0 (CH), 125.5(CH), 119.6 (C), 65.3 (CH), 60.8 (CH), 55.8 (CH), 42.9 (C), 36.8 (CH₂),32.2 (CH₃), 24.5 (CH₃), 15.4 (CH₃). IR (film): v/cm⁻¹ 2981, 2935, 2246,1672, 1447, 1428, 1402, 1301, 1229, 1065, 915, 722. LR-MS: 326.0 M+Na⁺.HR-MS (ESI) calculated for C₁₅H₁₇N₃O₂SNa: 326.0939 (M+Na⁺), found:326.0942.

Rac-(6S,7S,8aS)-6-(4-Chlorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.35 (2H, d, J=8.5 Hz), 7.07 (2H, d,J=8.5 Hz), 4.88 (1H, s), 4.39 (1H, dd, J=6.5, 11.5 Hz), 3.90 (1H, q,J=7.5 Hz), 3.06 (3H, s), 2.76 (1H, app t, J=12.0 Hz), 2.48 (1H, dd,J=6.5, 8.5 Hz), 1.70 (3H, s), 1.49 (3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.7 (C), 166.0 (C), 135.4 (C), 135.1 (C), 129.4 (2CH),127.5 (2CH), 119.7 (C), 69.2 (CH), 60.9 (CH), 56.3 (CH), 42.4 (C), 36.8(CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃). IR (film): v/cm⁻¹ 2981, 2919,2852, 2246, 1673, 1490, 1430, 1303, 1235, 1093, 731. LR-MS: 354.0 M+Na⁺.HR-MS (ESI) calculated for C₁₇H₁₈N₃O₂ClNa: 354.0985 (M+Na⁺), found:354.0981.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2-(3-(dimethylamino)propyl)-3,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 8:1 mixture of diastereomers, data for the major isomeris reported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.74 (1H, d, J=8.0 Hz), 6.56(1H, d, J=8.0 Hz), 6.52 (1H, s), 5.91 (2H, s), 4.80 (1H, s), 4.35 (1H,dd, J=6.5, 11.0 Hz), 4.02 (1H, q, J=7.5 Hz), 3.83 (1H, dt, J=7.5, 13.5Hz), 3.00 (1H, dt, J=7.5, 13.5 Hz), 2.74 (1H, app t, J=12.0 Hz), 2.40(1H, dd, J=6.5, 13.5 Hz), 2.20-2.30 (2H, m), 2.14 (6H, s), 1.70-1.80(2H, m), 1.62 (3H, s), 1.43 (3H, d, J=6.5 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 167.1 (C), 166.3 (C), 148.3 (C), 148.2 (C), 131.0 (C), 119.9 (C),119.7 (CH), 108.6 (CH), 106.3 (CH), 101.5 (CH₂), 69.4 (CH), 59.3 (CH),56.3 (CH₂), 56.2 (CH), 45.4 (2CH₃), 43.3 (C), 42.7 (CH₂), 36.6 (CH₂),25.9 (CH₂), 25.1 (CH₃), 16.0 (CH₃). IR (film): v/cm⁻¹ 2979, 2943, 2822,2781, 2244, 1672, 1491, 1448, 1427, 1245, 1037, 929, 811, 735. LR-MS:435.3 M+Na⁺. HR-MS (ESI) calculated for C₂₂H₂₈N₄O₄Na: 435.2008 (M+Na⁺),found: 435.2015.

Rac-(3R,6R,7S,8aS)-6-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as a 3:1 mixture of diastereomers, data for the major isomer isreported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, s), 6.34 (1H, s),5.98 (2H, s), 5.34 (1H, s), 4.36 (1H, dd, J=6.5, 12.0 Hz), 3.92 (1H, q,J=7.0 Hz), 3.04 (3H, s), 2.66 (1H, app t, J=13.0 Hz), 2.48 (1H, dd,J=6.5, 13.0 Hz), 1.74 (3H, s), 1.47 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.5 (C), 166.0 (C), 148.7 (C), 148.1 (C), 129.1 (C),119.7 (C), 115.0 (C), 113.5 (CH), 105.0 (CH), 102.3 (CH₂), 68.2 (CH),60.8 (CH), 56.4 (CH), 42.2 (C), 37.4 (CH₂), 31.8 (CH₃), 24.9 (CH₃), 15.5(CH₃). IR (film): v/cm⁻¹ 2982, 2246, 1675, 1503, 1478, 1429, 1402, 1307,1248, 1120, 1036, 928. LR-MS: 435.3 HR-MS (ESI) calculated forC₁₈H₁₈BrN₃O₄Na: 442.0378 (M+Na⁺), found: 442.0369.

Rac-(3R,6S,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(p-tolyl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.17 (2H, d, J=7.5 Hz), 7.01 (2H, d,J=7.5 Hz), 4.88 (1H, s), 4.38 (1H, dd, J=7.0, 11.0 Hz), 3.89 (1H, q,J=7.0 Hz), 3.04 (3H, s), 2.79 (1H, app t, J=12.5 Hz), 2.44 (1H, dd,J=6.5, 12.5 Hz), 2.32 (3H, s), 1.67 (3H, s), 1.47 (3H, d, J=7.0 Hz);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.7 (C), 166.2 (C), 138.9 (C), 134.0(C), 129.8 (2CH), 125.9 (2CH), 120.0 (C), 69.6 (CH), 60.9 (CH), 56.2(CH), 42.6 (C), 36.7 (CH₂), 32.1 (CH₃), 25.2 (CH₃), 21.3 (CH₃), 15.4(CH₃). IR (film): v/cm⁻¹ 3054, 2982, 2935, 2877, 2243, 1681, 1515, 1452,1430, 1402, 1306, 1246, 1230, 1063, 804, 734. LR-MS: 334.0 M+Na⁺. HR-MS(ESI) calculated for C₁₈H₂₁N₃O₂Na: 334.1531, found: 334.1536. Thestructure and relative configuration of this sample was confirmed bysingle-crystal X-ray analysis.

Rac-(3R,6S,7S,8aS)-6-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, 1:1 d₄-MeOD/CDCl₃): δ/ppm 6.61 (1H, d, J=7.0 Hz), 6.38(2H, m), 4.59 (1H, s), 4.28 (1H, m), 4.00 (4H, m), 3.69 (1H, q, J=9.0Hz),2.82 (3H, s), 2.48 (1H, app t, J=12.0 Hz), 2.23 (1H, dd, J=8.5, 12.0Hz), 1.45 (3H, s), 1.26 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 167.3 (C), 166.6 (C), 144.0 (C), 143.7 (C), 130.2 (C), 120.0 (C),119.1 (CH), 117.6 (CH), 114.9 (CH), 69.3 (CH), 64.3 (2CH₂), 60.8 (CH),56.1 (CH), 42.7 (C), 36.5 (CH₂), 31.9 (CH₃), 24.7 (CH₃), 14.9 (CH₃). IR(film): v/cm⁻¹ 3056.3, 2982.2, 2936.7, 2878.2, 2244.2, 1672.0, 1509.0,1450.8, 1432.5, 1307.3, 1287.9, 1067.0, 886.5. LR-MS: 378.1 M+Na⁺. HR-MS(ESI) calculated for C₁₉H₂₁N₃O₄Na: 378.1430, found: 378.1433.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-2-(2-morpholinoethyl)-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, 1:1 d₄-MeOD/CDCl₃): δ/ppm 6.61 (1H, d, J=9.5 Hz), 6.49(1H, d, J=9.5 Hz), 6.36 (1H, s), 5.77 (2H, s), 4.67 (1H, s), 4.31 (1H,dd, J=6.5, 11.0 Hz), 3.88 (1H, q, J=9.0 Hz), 3.80 (1H, m), 3.44-3.50(4H, m), 2.88-2.95 (1H, m), 2.55 (1H, app t, J=6.5 Hz), 2.20-2.45 (7H,m), 1.49 (3H, s), 1.31 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 167.4 (C), 166.5 (C), 148.2 (C), 148.1 (C), 131.0 (C), 120.2 (CH),120.0 (C), 108.5 (CH), 105.8 (CH), 101.5 (CH₂), 69.4 (CH), 66.9 (2CH₂),59.7 (CH), 56.4 (CH₂), 56.1 (CH), 53.7 (2CH₂), 42.8 (C), 41.6 (CH₂),36.5 (CH₂), 24.8 (CH₃), 15.6 (CH₃). IR (film): v/cm⁻¹ 2955.4, 2858.2,2812.5, 2243.7, 1672.0, 1491.0, 1448.4, 1426.9, 1295.8, 1245.8, 1115.3,1036.5, 922.1. LR-MS: 441.3 M+H⁺. HR-MS (ESI) calculated forC₂₃H₂₈N₄O₅Na: 463.1957, found 463.1946.

Rac-(3R,6S,7S,8aS)-6-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, d, J=8.0 Hz), 6.90 (1H, d,J=8.0 Hz), 6.83 (1H, s), 4.88 (1H, s), 4.36-4.43 (1H, dd, J=6.5, 11.5Hz), 3.92 (1H, q, J=7.0 Hz), 3.07 (3H, s), 2.76 (1H, app t, J=12.0 Hz),2.51 (1H, dd, J=6.5, 13.5 Hz), 1.71 (3H, s), 1.50 (3H, d, J=7.0 Hz);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.8 (C), 165.9 (C), 144.2 (C), 144.1(C), 133.3 (C), 131.7 (CF₂, t, J=255 Hz), 121.9 (CH), 119.6 (C), 110.0(CH), 107.4 (CH), 69.4 (CH), 60.5 (CH), 56.3 (CH), 42.6 (C), 36.9 (CH₂),32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃). IR (film): v/cm⁻¹ 2984, 2939, 2246,1674, 1500, 1452, 1429, 1403, 1241, 1150, 912, 732. LR-MS: 400.2(M+Na⁺); HR-MS (ESI) calculated for C₁₈H₁₇N₃O₄F₂Na: 400.1085, found:400.1092.

Rac-(3R,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.73 (lH, d, J=9.0 Hz), 6.2-7.0 (2H, brs), 5.95 (2H, d, J=9.0 Hz), 5.35 (1H, s), 4.62 (1H,1H, m), 3.88 (1H, q,J=7.5 Hz), 3.29 (1H, d, J=9.5 Hz), 3.21 (1H, d, J=9.5 Hz), 3.05 (3H, s),2.58-2.62 (1H, m), 2.26 (1H, app t, J=12.0 Hz), 1.52 (3H, d, J=7.5 Hz),0.88 (9H, s), 0.01 (3H, s), −0.02 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 166.4 (C), 166.2 (C), 148.0 (2C), 128.2 (C), 121.7 (C), 108.5(CH), 101.5 (CH₂), 66.6 (CH), 63.5 (CH₂), 61.1 (CH), 57.0 (CH), 49.2(C), 33.1 (CH₂), 32.1 (CH₃), 25.7 (3CH₃), 18.2 (C), 15.4 (CH₃), −5.6(2CH₃), 2 aromatic CH not seen. IR (film): v/cm⁻¹ 2930, 2884, 2857,2240, 1678, 1490, 1448, 1402, 1245, 1105, 1039, 928, 840, 780, 732.LR-MS: 494.3 (M+Na⁺); HR-MS (ESI) calculated for C₂₄H₃₃N₃O₅SiNa:494.2087, found: 494.2068.

Rac-(3R,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(methoxymethyl)-2,3-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.78 (1H, d, J=8.0 Hz), 6.65 (1H, d,J=8.0 Hz), 6.59 (1H, s), 5.95 (2H, s), 5.03 (1H, s), 4.36 (1H, dd,J=7.0, 11.0 Hz), 3.88 (1H, q, J=7.0 Hz), 3.62 (2H, s), 3.48 (3H, s),3.02 (3H, s), 2.74 (1H, app t, J=11.5 Hz), 2.67 (1H, dd,J=7.5, 14.0 Hz),1.44 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.7 (C), 166.2(C), 148.3 (C), 148.2 (C), 130.8 (C), 120.0 (CH), 118.3 (C), 108.8 (CH),106.4 (CH), 101.5 (CH₂), 74.8 (CH₂), 65.4 (CH), 60.8 (CH), 59.8 (CH₃),56.8 (CH), 48.7 (C), 33.7 (CH₂), 32.1 (CH₃), 15.3 (CH₃).

Rac-(3R,6R,7S,8aS)-6-(Benzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, d₆-DMSO, 390K): δ/ppm 6.85 (2H, br s), 6.65 (1H, br s),6.00 (1H, s), 5.92 (1H, s), 4.96 (1H, s), 4.67 (1H, dd, J=6.5, 10.5 Hz),3.95 (1H, q, J=7.0 Hz), 2.97 (3H, s), 2.58-2.67 (1H, m), 2.44-2.55 (1H,m), 1.72 (3H, s), 1.46 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz, d₆-DMSO,390K): δ/ppm 166.8 (C), 166.6 (C), 147.9 (C), 145.0 (C), 122.1 (CH),121.1 (C), 120.5 (CH), 108.7 (CH), 101.4 (CH₂), 65.6 (CH), 60.6 (CH),56.4 (CH), 42.7 (C), 38.1 (CH₂), 31.8 (CH₃), 25.0 (CH₃), 15.6 (CH₃). IR(film): v/cm⁻¹ 3056, 2981, 2895, 2244, 1672, 1460, 1432, 1402, 1251,1066, 928, 731. LR-MS: 342.1 (M+H⁺); HR-MS (ESI) calculated forC₁₈H₁₉N₃O₄Na: 364.1273, found: 364.1267.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-butyl-3,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.79 (1H, d, J=9.0 Hz), 6.60 (1H, d,J=9.0 Hz), 6.55 (1H, s), 5.96 (2H, s), 4.82 (1H, s), 4.38 (1H, dd,J=6.5, 11.0 Hz), 3.95 (1H, app q, J=7.0 Hz), 2.99 (1H, m), 2.81 (1H, appt, J=7.0 Hz), 2.43 (1H, dd, J=6.5, 13.5 Hz), 1.60 (2H, m), 1.56 (3H, s),1.45 (3H, d, J=7.0 Hz) 1.38 (2H, m), 0.96 (3H, t, J=7.2 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 167.2 (C), 166.3 (C), 148.6 (C), 148.4 (C),131.1 (C), 120.0 (CH), 119.9 (C), 108.8 (CH), 106.4 (CH), 101.7 (CH₂),69.7 (CH), 59.0 (CH), 56.5 (CH), 44.8 (C), 42.9 (CH₂), 36.9 (CH₂), 30.0(CH₂), 25.4 (CH₃), 20.2 (CH₂), 16.2 (CH₃). 13.9 (CH₃), LR-MS: 406.2M+Na⁺; IR (film): v/cm⁻¹ 2982, 2917, 2244, 1671, 1491, 1447, 1246, 1037,925, 721 v/cm⁻¹. HR-MS (ESI) calculated for C₂₁H₂₅N₃O₄Na: 406.1713(M+Na⁺), found: 406.1730.

Rac-(3R,6S,7S,8aS)-6-(4-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.05 (2H, d, J=8.5 Hz), 6.88 (2H, d,J=8.5 Hz), 4.88 (1H, s), 4.39 (1H, dd, J=6.5, 11.5 Hz), 3.90 (1H, q,J=7.5 Hz), 3.79 (3H, s), 3.05 (3H, s), 2.80 (1H, app t, J=12.0 Hz), 2.46(1H, dd, J=6.5, 8.5 Hz), 1.70 (3H, s), 1.48 (3H, d, J=7.5 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 166.6 (C), 166.2 (C), 159.9 (C), 128.9 (C),127.2 (2CH), 119.9 (C), 114.4 (2CH), 69.3 (CH), 60.9 (CH), 56.1 (CH),55.2 (CH₃), 42.6 (C), 36.6 (CH₂), 32.1 (CH₃), 25.1 (CH₃), 15.3 (CH₃). IR(film): v/cm⁻¹ 2981, 2919, 2852, 2246, 1673, 1490, 1303, 1235, 1093,756. HR-MS (ESI) calculated for C₁₈H₂₁N₃O₃Na: 350.1475 (M+Na⁺), found:350.1465.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-ethyl-2,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Prepared from the corresponding pyrrolidine ester and 2-chlorobutanoylchloride by conducting the reaction with methylamine at 60° C.overnight. Isolated as a 9:1 mixture of diastereomers; NMR data for themajor isomer is reported. ¹H-NMR (600 MHz, CDCl₃) δ 6.79 (d, J=8.0 Hz,1H), 6.63 (dd, J=8.0, 1.9 Hz, 1H), 6.56 (t, J=1.9 Hz, 1H), 5.96 (s, 2H),4.83 (s, 1H), 4.41 (dd, J=8.0, 1.9 Hz, 1H), 3.77 (dd, J=7.5, 6.3 Hz,1H), 3.08 (s, 3H), 2.76 (dd, J=13.0, 11.7 Hz, 1H), 2.45 (dd, J=13.2, 6.7Hz, 1H), 1.95-1.92 (m, 1H), 1.91-1-85 (m, 1H), 1.66 (s, 3H), 1.07 (t,J=7.4 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.4 (C), 166.2 (C),148.4 (C), 148.3 (C), 131.0 (C), 120.0 (CH), 119.9 (C), 108.8 (CH),106.3 (CH), 101.6 (CH₂), 69.9 (CH), 66.8 (CH), 56.3 (CH), 42.7 (C), 37.0(CH₂), 33.5 (CH₃), 25.4 (CH₃), 24.4 (CH₂), 10.6 (CH₃) ppm; IR (film)v/cm⁻¹ 2929, 2245, 1672, 1491, 1446, 1402, 1246, 1038, 916, 821, 730cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁N₃O₄Na⁺ (M+Na) 378.1430, found378.1433.

Rac-(3R,6S,7S,8aS)-2-allyl-6-(benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

The cyclization to the diketopiperazine was performed in a THF/H₂O (1:1)solvent mixture at 80° C., overnight. ¹H-NMR (600 MHz, CDCl₃) δ6.80-6.78 (m, 1H), 6.63-6.61 (m, 1H), 6.56 (d, J=1.6 Hz, 1H), 5.98-5.96(m, 2H), 5.81-5.74 (m, 1H), 5.27 (dd, J=10.2, 1.1 Hz, 1H), 5.24 (dd,J=17.0, 1.1 Hz, 1H), 4.84 (s, 1H), 4.50 (ddt, J=15.3, 5.3, 1.4 Hz, 1H),4.41 (dd, J=11.7, 6.7 Hz, 1H), 3.97 (q, J=7.4 Hz, 1H), 3.68 (dd, J=15.2,6.8 Hz, 1H), 2.82 (dd, J=13.3, 11.5 Hz, 1H), 2.46 (dd, J=13.3, 6.8 Hz,1H), 1.68 (s, 3H), 1.48 (d, J=7.4 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 167.0 (C), 166.1 (C), 148.4 (C), 148.3 (C), 131.8 (CH), 131.0 (C),119.9 (CH), 119.3 (CH₂), 108.8 (CH), 106.3 (CH), 101.6 (CH₂), 69.6 (CH),58.2 (CH), 56.3 (CH), 54.7 (C), 47.1 (CH₂), 42.8 (C), 36.7 (CH₂), 25.4(CH₃), 16.0 (CH₃) ppm; IR (film) v/cm⁻¹ 2924, 2853, 2244, 1674, 1505,1448, 1427, 1294, 1246, 1184, 1101, 1038, 933, 859, 809, 735 cm⁻¹; HRMS(ESI) calcd for C₂₀H₂₁N₃O₄Na⁺ (M+Na) 390.1430, found 390.1438.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-3,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Cyclization to the diketopiperazine was performed using cyclopropylamine(3.5 equiv) in a THF/H₂O (1:1) solvent mixture that was heated from80-100° C. over 2 d. ¹H-NMR (500 MHz, CDCl₃) δ 6.76 (d, J=8.0 Hz, 1H),6.56 (d, J=8.0 Hz, 1H), 6.47 (s, 1H), 5.95 (s, 2H), 4.80 (s, 1H), 4.38(dd, J=11.3, 6.7 Hz, 1H), 3.98 (q, J=7.3 Hz, 1H), 2.74-2.69 (m, 2H),2.45 (dd, J=13.3, 6.7 Hz, 1H), 1.65 (s, 3H), 1.49 (d, J=7.3 Hz, 3H),1.09 (dq, J=9.5, 6.6 Hz, 1H), 0.88-0.83 (m, 1H), 0.79 (dq, J=9.5, 6.5Hz, 1H), 0.58 (dq, J=10.4, 5.2 Hz, 1H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ168.2 (C), 167.2 (C), 148.3 (C), 148.2 (C), 130.9 (C), 119.9 (CH),119.8 (CH), 108.7 (CH), 106.1 (CH), 101.5 (CH₂), 69.4 (CH), 59.8 (CH),56.7 (CH), 42.7 (C), 36.7 (CH₂), 28.0 (CH), 25.2 (CH₃), 16.2 (CH₃), 8.7(CH₂), 5.7 (CH₂) ppm; IR (film) v/cm⁻¹ 2984, 1675, 1490, 1424, 1376,1245, 1189, 1036, 932, 733 cm⁻¹; HRMS (ESI) calcd for C₂₀H₂₁N₃O₄Na⁺(M+Na) 390.1430, found 390.1433.

Rac-(3R,6S,7S,8aS)-6-(3,4-bis(allyloxy)phenyl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.86 (d, J=8.2 Hz, 1H), 6.65-6.63 (m, 2H),6.09-6.01 (m, 2H), 5.39 (dd, J=17.2 Hz, 1.1 Hz, 1H), 5.37 (dd, J=17.3Hz, 1.2 Hz, 1H), 5.26 (app. dt, J=10.6, 0.2 Hz, 2H), 4.85 (s, 1H),4.60-4.57 (m, 4H), 4.37 (dd, J=11.3, 6.8 Hz, 1H), 3.91 (q, J=7.2 Hz,1H), 3.06 (s, 3H), 2.78 (app t, J=12.2 Hz, 1H), 2.44 (dd, J=13.3, 6.8Hz, 1H), 1.68 (s, 3H), 1.49 (d, J=7.2 Hz, 3H) ppm; ¹³C-NMR (126 MHz,CDCl₃) δ166.8 (C), 166.3 (C), 149.2 (C), 148.7 (C), 133.4 (CH), 133.4(CH), 129.6 (C), 119.9 (C), 118.7 (CH), 117.9 (CH₂), 117.9 (CH₂), 113.9(CH), 112.4 (CH), 70.2 (CH₂), 69.9 (CH₂), 69.5 (CH), 61.1 (CH), 56.2(CH), 42.7 (C), 36.7 (CH₂), 32.3 (CH₃), 25.3 (CH₃), 15.4 (CH₃) ppm; IR(film) v/cm⁻¹ 2983, 1672, 1515, 1451, 1426, 1306, 1259, 1224, 1206,1139, 1017, 996, 924, 806, 732 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₇N₃O₄Na⁺(M+Na) 432.1899, found 432.1888.

Rac-(3R,6S,7S,8aS)-6-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 8:1 mixture of diasteromers; NMR data for the majorisomer is reported. ¹H-NMR (500 MHz, CDCl₃) δ 6.34 (s, 1H), 6.24 (s,1H), 5.97 (s, 2H), 4.81 (s, 1H), 4.36 (dd, J=11.3, 6.6 Hz, 1H), 3.92 (q,J=7.3 Hz, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.78 (app. t, J=12.4 Hz, 1H),2.46 (dd, J=13.3, 6.6 Hz, 1H), 1.68 (s, 3H), 1.49 (d, J=7.3 Hz, 3H) ppm;¹³C-NMR (126 MHz, CDCl₃) δ166.9 (C), 166.2 (C), 149.5 (C), 143.8 (C),135.9 (C), 131.6 (C), 119.9 (C), 107.0 (CH), 102.0 (CH₂), 99.7 (CH),69.8 (CH), 61.0 (CH), 56.8 (CH₃), 56.3 (CH), 42.8 (C), 36.8 (CH₂), 32.3(CH₃), 25.4 (CH₃), 15.5 (CH₃) ppm; IR (film) v/cm⁻¹ 2981, 1143, 1673,1512, 1452, 1433, 1402, 1324, 1240, 1199, 1135, 1093, 1043, 927, 735cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁N₃O₅Na⁺ (M+Na) 394.1379, found394.1371.

Rac-(3R,6S,7S,8aS)-6-(2,3-dihydro-1H-inden-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) □ 7.19 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 6.93 (d,J=7.7 Hz, 1H), 4.89 (s, 1H), 4.38 (dd, J=11.6, 6.7 Hz, 1H), 3.91 (q,J=7.3 Hz, 1H), 3.07 (s, 3H), 2.90-2.80 (m, 5H), 2.45 (dd, J=13.3, 6.6Hz, 1H), 2.05 (app. quintett, J=7.5 Hz, 2H), 1.69 (s, 3H), 1.49 (d,J=7.3 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ166.8 (C), 166.3 (C), 145.5(C), 145.2 (C), 134.8 (C), 125.0 (CH), 123.9 (CH), 122.1 (CH), 120.1(C), 70.1 (CH), 61.0 (CH), 56.3 (CH), 42.8 (C), 36.8 (CH₂), 33.0 (CH₂),32.8 (CH₂), 32.2 (CH₃), 25.4 (CH₃), 25.4 (CH₂), 15.5 (CH₂) ppm; IR(film) v/cm⁻¹ 1940, 1673, 1431, 1402, 1306, 1239, 1062, 814, 733 cm⁻¹;HRMS (ESI) calcd for C₂₀H₂₃N₃O₂Na⁺ (M+Na) 360.1688, found 360.1684.

Rae(3R,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(1-(phenylsulfonyl)-1H-indol-3-yl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 7:1 mixture of diasteromers; NMR data for the majorisomer is reported. ¹H-NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.2 Hz, 1H),7.77 (d, J=7.5 Hz, 2H), 7.51 (app. t, J=7.3 Hz, 1H), 7.46-7.39 (m, 4H),7.31 (app. t, J=7.3 Hz, 1H), 7.25 (app. t, J=7.3 Hz, 1H), 5.18 (s, 1H),4.40 (dd, J=12.4, 6.3 Hz, 1H), 3.92 (q, J=7.4 Hz, 1H), 3.09 (s, 3H),2.83 (app. t, J=11.9 Hz, 1H), 2.57 (dd, J=13.3, 6.3 Hz, 1H), 1.73 (s,3H), 1.49 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ166.7 (C), 166.0 (C),137.9 (C), 135.4 (C), 134.1 (CH), 129.5 (CH), 126.8 (CH), 125.6 (CH),124.1 (CH), 123.9 (CH), 119.9 (CH), 119.6 (C), 119.5 (C), 119.4 (C),114.1 (CH), 62.4 (CH), 60.9 (CH), 56.2 (CH), 42.2 (C), 38.1 (CH₂), 32.3(CH₃), 25.1 (CH₃), 15.7 (CH₃) ppm; IR (film) v/cm⁻¹ 2982, 1675, 1448,1367, 1307, 1175, 1124, 1095, 977, 748, 725 cm⁻¹; HRMS (ESI) calcd forC₂₅H₂₄N₄O₄SNa⁺ (M+Na) 499.1416, found 499.1412.

Alternate Procedure for Forming Diketopiperazines from SubstitutedProlidine Esters and Protected α-Amino Acids.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-benzyl-2,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

To a solution of N-Boc-phenylalanine (263 mg, 1.00 mmol, 1.5 equiv) indry CH₂Cl₂ (2 mL) at 0° C. was added N,N-diisopropylethylamine (0.12 mL,0.66 mmol, 1 equiv) and BOPCl (253 mg, 1.00 mmol, 1.5 equiv) and thereaction was allowed to warm to room temperature over 1 h. Afterrecooling to 0° C. additional N,N-diisopropylethylamine (0.23 mL, 1.3mmol, 2 equiv) was added, followed by the dropwise addition of asolution of the corresponding pyrrolidine ester (200 mg, 0.66 mmol, 1equiv) in CH₂Cl₂(1.3 mL). The reaction was allowed to warm to roomtemperature overnight, after which time TLC analysis showed fullconversion of the starting material. After an extractive work-up(CH₂Cl₂/water), the crude product was filtered through a silica gel plugusing hexanes/ethyl acetate (1:1) as the eluent and the volatiles wereremoved in vacuo. The crude acylated pyrrolidine ester was dissolved indry CH₂Cl₂ (2.1 mL) and cooled to 0° C. Trifluoroacetic acid (0.8 mL)was added, the reaction allowed to warm to rt over 3 h, and thevolatiles were removed under reduced pressure. The resulting residue wasdissolved in a 4:1 mixture i-BuOH/toluene (18 mL) containingN,N-diisopropylethylamine (0.46 mL, 2.65 mmol, 4 equiv). The vial wassealed with a teflon cap and heated to 100° C. overnight. After anextractive work up (CH₂Cl₂/water) and concentration, two diastereomericDKPs were separated by silica gel chromatography (eluent: hexanes/EtOAc1:3).

NMR data for diastereomer A: ¹H-NMR (600 MHz, CDCl₃) δ 7.38-7.35 (m,3H), 7.26-7.25 (m, 2H), 7.00 (d, J=3.7 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H),6.63 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 5.92 (s, 2H), 4.71 (s, 1H), 4.29(app. q, J=4.2 Hz, 1H), 3.31 (dd, J=13.9, 4.6 Hz, 1H), 2.95 (dd, J=13.9,4.4 Hz, 1H), 2.64 (dd, J=11.9, 6.2 Hz, 1H), 2.44 (app. t, J=12.5 Hz,1H), 2.05 (dd, J=13.0, 6.3 Hz, 1H), 1.32 (s, 3H) ppm. NMR data fordiastereomer B: ¹H-NMR (600 MHz, CDCl₃) δ 7.37-7.34 (m, 2H), 7.32-7.29(m, 1H), 7.22-7.19 (m, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.64 (dd, J=8.8, 1.7Hz, 1H), 6.60 (d, J=1.8 Hz, 1H), 6.00 (d, J=1.5 Hz, 1H), 5.99 (d, J=1.5Hz, 1H), 5.69 (broad s, 1H), 4.91 (s, 1H), 4.40 (dd, J=11.3, 6.9 Hz,1H), 4.32 (dd, J=10.2, 4.2 Hz, 1H), 3.51 (dd, J=14.7, 3.9 Hz, 1H), 2.79(dd, J=11.5, 4.1 Hz, 1H), 2.77 (dd, J=10.3, 4.4 Hz, 1H), 2.40 (dd,J=13.4, 6.8 Hz, 1H), 1.68 (s, 3H) ppm.

Both DKP products were individually methylated in a separate reactionvessel by the following procedure: To the intermediate DKP (91 mg, 0.23mmol, 1 equiv) in acetone (2.8 mL) was added K₂CO₃ (620 mg, 4.5 mmol, 20equiv) and Mel (1.4 mL, 23 mmol, 100 equiv) and the reaction was stirredfor 2 d at room temperature with the exclusion of light. After anextractive work up (CH₂Cl₂/water), each diasteromeric DKP was obtainedas amorphous solid.

Diastereomer A: ¹H-NMR (500 MHz, CDCl₃) δ 7.34-7.31 (m, 3H), 7.18-7.13(m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.51 (s, 1H),5.95 (s, 2H), 4.65 (s, 1H), 4.18 (t, J=4.1 Hz, 1H), 3.28 (dd, J=14.1,3.9 Hz, 1H), 3.14-3.10 (m, 4H), 2.40-2.39 (m, 2H), 2.04-2.01 (m, 1H),1.26 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ166.5 (C), 165.5 (C), 148.3(C), 148.2 (C), 135.4 (C), 131.1 (C), 129.9 (CH), 129.2 (CH), 128.1(CH), 120.0 (C), 119.9 (CH), 108.8 (CH), 106.1 (CH), 101.5 (CH₂), 69.5(CH), 66.4 (CH), 55.4 (CH), 42.3 (C), 36.8 (CH₂), 36.4 (CH₂), 32.4(CH₃), 24.8 (CH₃) ppm; IR (film) v/cm⁻¹ 2934, 2247, 1673, 1505, 1491,1446, 1403, 1304, 1247, 1102, 1053 cm⁻¹; HRMS (ESI) calcd forC₂₄H₂₃N₃O₄Na⁺ (M+Na) 440.1586, found 440.1580. Diastereomer B: ¹H-NMR(500 MHz, CDCl₃) δ 7.26-7.19 (m, 3H), 7.14-7.11 (m, 2H), 6.76 (d, J=8.0Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 5.99-5.96 (m, 2H), 4.82(s, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.37 (dd, J=11.3, 6.8 Hz, 1H), 3.48(dd, J=16.0, 5.6 Hz, 1H), 3.42 (dd, J=16.0, 5.5 Hz, 1H), 3.04 (s, 3H),2.81 (dd, J=13.1, 11.5 Hz, 1H), 2.46 (dd, J=13.4, 6.6 Hz, 1H), 1.66 (s,3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ168.1 (C), 165.8 (C), 148.3 (2×C),136.5 (C), 130.8 (C), 129.0 (CH), 128.8 (CH), 127.1 (CH), 120.1 (C),120.0 (CH), 108.8 (CH), 106.7 (CH), 101.2 (CH₂), 69.8 (CH), 61.3 (CH),57.4 (CH), 42.8 (C), 37.0 (CH₂), 33.5 (CH₂), 30.9 (CH₃), 25.6 (CH₃) ppm;IR (film) v/cm⁻¹ 1675, 1504, 1491, 1448, 1390, 1306, 1244, 1039, 912,733, 700 cm⁻¹; HRMS (ESI) calcd for C₂₄H₂₃N₃O₄Na⁺ (M+Na) 440.1586, found440.1577.

Example 4

General Procedure for Synthesis of Epidithiodiketopiperazines.

MethylRac-(3S,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

To a suspension of elemental sulfur (32 mg, 1.0 mmol) in dry THF (5 mL)was added a solution of NaHMDS (0.25 mL, 2 M in THE) at roomtemperature. After 1 min, a solution of the diketopiperazine (35 mg, 0.1mmol, in 2 mL THF) was added, followed by a second aliquot of NaHMDS(0.25 mL, 2 M in THF) within another 2 min. The resulting orange-brownsolution was stirred for 30 min at rt, cooled to 0° C. and quenched byaddition of aqueous NH₄Cl. After extractive work-up (CH₂Cl₂/water) andevaporation of the solvent, a yellow residue was obtained. This residuewas re-dissolved in a mixture of MeOH/THF (5 mL) to which NaBH₄ (350 mg,1 mmol) was added portionwise at 0° C. After stirring for 30 min, thismixture was quenched with aqueous NH₄Cl, extracted (CH₂Cl₂/water) andthe extract was dried over Na₂SO₄. After evaporation of the solvent, ayellow residue was obtained, which was subsequently dissolved in EtOAc(10 mL). A solution of KI₃ (0.5 M, 2 mL) in water was added and thebiphasic system was stirred at rt for 15 min, after which time 3 mL ofsaturated aqueous Na₂S₂O₃ was added to give a pale yellow EtOAc layer.Aqueous extraction and evaporation of the organic phase gives a yellowoil, which was purified by preparative TLC (Et₂O/CH₂Cl₂) to give thetitle compound as a yellow oil.

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.41 (2H, m), 7.03 (2H, t, J=9.0 Hz),5.09 (1H, s), 3.36 (3H, s), 3.34 (1H, d, J=14.5 Hz), 3.25 (1H, d, J=14.5Hz), 3.11 (3H, s), 1.97 (3H, s), 1.55 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 171.8 9 (C), 166.2 (C), 163.1 (C), 162.6 (C, d, J=250 Hz), 131.8(C), 129.4 (2CH, d, J=8 Hz), 115.5 (2CH, d, J=22 Hz), 74.6 (C), 73.4(C), 72.4 (CH), 55.1 (C), 52.3 (CH₃), 38.9 (CH₂), 27.8 (CH₃), 25.5(CH₃), 18.4 (CH₃). IR (film): v/cm⁻¹ 2951, 1736, 1692, 1606, 1511, 1255,1228, 1161, 1129, 848, 733. LR-MS: 432.85 (M+Na⁺); HR-MS (ESI)calculated for C₁₈H₁₉N₂O₄FS₂Na: 433.0668, found: 433.0660.

Example 5

Alternate Simplified General Procedure for Synthesis ofEpidithiodiketopiperazines.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-ethyl-2,7-dimethyl-1,4-dioxo-hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

To a suspension of S₈ (83 mg, 0.32 mmol) in dry THF (3.4 mL) was added asolution of NaHMDS (1.7 mL, 0.93 mmol, 3.3 equiv, 0.56 M in toluene) atroom temperature over 40 sec. After 1 min, a solution of thediketopiperazine (100 mg, 0.28 mmol, in 2.6 mL THF) was added dropwise,followed by a second aliquot of NaHMDS (1.1 mL, 0.62 mmol, 2.2 equiv,0.56 M in toluene) within another 30-40 sec. The resulting orange-yellowsolution was stirred for 50 min at rt and quenched by addition ofsaturated aqueous NH₄Cl. After extractive work-up (CH₂Cl₂/water) andevaporation of the solvent, a yellow-brown amorphous residue wasobtained. This residue was evaporated onto 2.2 g SiO₂ and placed on topof a filter frit containing 12 g SiO₂. Washing of this SiO₂ plug with150 mL of hexanes removes the majority of HMDS-related material.Subsequent washing with 150 mL of MeCN elutes the sulfidated products asa mixture of epidi- and epitrisulfide products (epidi:epitri usually9:1). These products were separated by preparative TLC (2-4%EtOAc/CH₂Cl₂). The desired epidisulfide product (R_(f)˜0.3) was isolatedas an off-white solid (purity 95%) after removal of the volatiles invacuo.

¹H-NMR (600 MHz, CDCl₃) δ 6.88 (s, 1H), 6.84 (app. s, 2H), 5.99 (app. m,2H), 4.83 (s, 1H), 3.28 (d, J 15.0 Hz, 1H), 3.10 (s, 3H), 3.01 (d,J=15.0 Hz, 1H), 2.39 (m, 1H), 2.30 (m, 1H), 1.68 (s, 3H), 1.25 (t, J=7.2Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.6 (C), 161.0 (C), 148.6 (C),148.3 (C), 127.5 (C), 120.8 (CH), 120.4 (C), 108.6 (CH), 107.3 (CH),101.6 (CH₂), 78.0 (C), 73.5 (C), 72.6 (CH), 44.5 (C), 42.9 (CH₂), 28.8(CH₃), 25.4 (CH₂), 24.9 (CH₃), 9.9 (CH₃) ppm; IR (film) v/cm⁻¹ 2917,1685, 1558, 1506, 1491, 1357, 1249, 1001, 928 cm⁻¹; HRMS (ESI) calcd forC₁₉H₁₉N₃O₄S₂Na⁺ (M+Na) 440.0715, found 440.0718.

At the end of the concentration process, MeOH (1-2 mL) and CH₂Cl₂ (1-2mL) can be added and then again removed in vacuo to facilitate theformation of a colorless powder. In other cases, the epidi- andepitrisulfide products can be separated by column chromatography onsilica gel using a mixtures of CH₂Cl₂ and EtOAc as the eluent. Generallyeither of the two procedures described above can be used to prepare theepidithiodiketopiperazine products.

tert-ButylRac-(3S,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52-7.55 (2H, m), 7.09 (2H, t, J=8.5Hz), 5.04 (1H, s), 3.36 (1H, d, J=14.5 Hz), 3.31 (1H, d, J=14.5 Hz),3.14 (3H, s), 1.99 (3H, s), 1.56 (3H, s), 1.17 (9H, s); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 170.4 (C), 166.3 (C), 163.0 (C), 161.7 (C, d, J=247Hz), 132.3 (C), 130.4 (2CH, d, J=8 Hz), 115.5 (2CH, d, J=22 Hz), 82.2(C), 74.4 (C), 73.5 (C), 72.2 (CH), 55.0 (C), 39.4 (CH₂), 27.8 (CH₃),27.5 (3CH₃), 26.6 (CH₃), 18.3 (CH₃). IR (film): v/cm⁻¹ 2977, 2935, 1693,1511, 1367, 1310, 1229, 1132, 847. LR-MS: 475.1 (M+Na); HR-MS (ESI)calculated for C₂₁H₂₅N₂O₄FS₂Na: 475.1137, found: 475.1132.

MethylRac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.98 (1, s), 6.87 (1H, d, J=8.0 Hz), 6.76(1H, d, J=8.0 Hz), 5.96 (2H, s), 5.03 (1H, s), 3.42 (3H, s), 3.34 (1H,d, J=14.0 Hz), 3.22 (1H, d, J=14.0 Hz), 3.10 (3H, s), 1.96 (3H, s), 1.52(3H); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.6 (C), 166.3 (C), 163.1 (C),147.9 (C), 147.6 (C), 129.6 (C), 121.3 (CH), 108.2 (CH), 108.0 (CH),101.3 (CH₂), 74.6 (C), 73.4 (C), 72.9 (CH), 55.1 (C), 52.3 (CH₃), 38.8(CH₂), 27.8 (CH₃), 25.4 (CH₃), 18.4 (CH₃). IR (film): v/cm⁻¹ 2953, 1736,1692, 1490, 1447, 1356, 1250, 1038. LR-MS: 459.2 M+Na⁺; HR-MS (ESI)calculated for C₁₉H₂₀N₂O₆S₂Na: 459.0660, found: 459.0652.

MethylRac-(3S,6S,7S,8aS)-6-(5-bromo-2-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.54 (1H, s), 7.34 (1H, d, J=9.0 Hz),6.70 (1H, d, J=9.0 Hz), 5.52 (11, s), 3.78 (3H, s), 3.33 (3H, s), 3.26(11, d, J=14.5 Hz), 3.21 (1H, d, J=14.5 Hz), 3.09 (3H, s), 1.96 (3H, s),1.52 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.7 (C), 166.3 (C),162.8 (C), 155.5 (C), 132.1 (CH), 130.9 (CH), 126.9 (C), 113.2 (C),111.8 (CH), 74.8 (C), 73.3 (C), 67.2 (CH), 55.7 (CH₃), 54.4 (C), 52.2(CH₃), 40.6 (CH₂), 27.8 (CH₃), 25.0 (CH₃), 18.4 (CH₃). IR (film): v/cm⁻¹2939, 1734, 1692, 1489, 1356, 1253, 1129, 1028, 914. LR-MS: 523.2(M+Na⁺); HR-MS (ESI) calculated for C₁₉H₂₁N₂O₅S₂BrNa: 522.9973 (M+Na⁺),found: 522.9972.

MethylRac-(3S,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(pyridin-3-yl)hexahydro-6H-3,8a-epidithio-pyrrolo[1,2-a]pyrazine-7-carboxylate

Isolated as a 4:1 mixture of diastereomers, data for the major isomer isreported. ^(L)H-NMR (500 MHz, CDCl₃): δ/ppm 8.63 (1H, d, J=2.0 Hz), 8.54(1H, dd, J=2.0, 5.0 Hz), 7.81 (1H, d, J=8.0 Hz), 7.27-7.30 (1H, m), 5.10(1H, s), 3.36 3H, s), 3.25-3.34 (2H, m), 3.10 (3H, s), 1.96 (3H, s),1.57 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.4 (C), 166.2 (C),163.1 (C), 149.8 (CH), 149.2 (CH), 135.1 (CH), 131.8 (C), 123.5 (CH),74.6 (C), 73.4 (C), 70.5 (CH), 55.1 (C), 52.5 (CH₃), 39.1 (CH₂), 27.8(CH₃), 25.5 (CH₃), 18.3 (CH₃). IR (film): v/cm⁻¹ 2927, 1735, 1690, 1354,1309, 1261, 1129, 916. LR-MS: 416.1 (M+Na⁺); HR-MS (ESI) calculated forC₁₇H₁₉N₃O₄S₂Na: 416.0715 (M+Na⁺), found: 416.0715.

Rac-(3S,6S,7S,8aS,9S)-2,3,7-trimethyl-1,4-dioxo-6-phenylhexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.46-7.38 (5H, m), 4.91 (1H, s), 3.32(1H, d, J=14.5 Hz), 3.09 (3H, s), 3.00 (1H, d, J=14.9 Hz), 1.94 (3H, s),1.69 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C), 162.2 (C),133.8 (C), 129.6 (CH), 129.1 (2CH), 126.9 (2CH), 120.2 (C), 73.4 (C),72.5 (CH), 44.5 (C), 43.0 (CH₂) 29.8 (C), 27.9 (CH₃), 24.9 (CH₃), 18.2(CH₃); IR (film): v/cm⁻¹ 2917, 2849, 2361, 2341, 2241, 1705, 1680;LR-MS: 382.0 [M+Na]⁺; HR-MS (ESI) calculated for C₁₇H₁₇N₃O₂S₂Na:382.0660, found: 382.0671.

Rac(3S,6S,7S,8aS,9S)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.37 (2H, dd, J=5.4, 8.4 Hz), 7.13 (2H,t, J=8.7 Hz), 4.89 (1H, s), 3.31 (1H, d, J=14.7 Hz), 3.08 (3H, s), 2.99(1H, d, J=15.0 Hz), 1.94 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.6 (C), 163.4 (C, d, J=247 Hz), 162.2 (C), 129.6 (C, d,J=3 Hz), 128.8 (2CH, d, J=8 Hz), 120.2 (C), 116.2 (2CH, d, J=22 Hz),73.52 (C), 73.46 (C), 71.9 (CH), 44.5 (C), 42.9 (CH₂), 27.9 (CH₃), 24.7(CH₃), 18.2 (CH₃); IR (film): v/cm⁻¹ 2991, 2356, 2239, 1706, 1682, 1512;LR-MS: 400.0 [M+Na]⁺; HR-MS (ESI) calculated for C₁₇H₁₆FN₃O₂S₂:400.0566, found: 400.0582.

Rac-(3S,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

Major ETP stereoisomer. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.96 (1H, s),6.91 (2H, app. s), 6.06 (2H, s), 4.89 (1H, s), 3.36 (1H, d, J=14.5 Hz),3.14 (3H, s), 3.06 (1H, d, J=14.5 Hz), 2.00 (3H, s), 1.73 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.6 (C), 162.1 (C), 148.6 (C), 148.3(C), 127.5 (C), 120.7 (CH), 120.3 (C), 108.6 (CH), 107.2 (CH), 101.6(CH₂), 73.4 (C), 73.3 (C), 72.4 (CH), 44.4 (C), 42.8 (CH₂), 27.8 (CH₃),24.8 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2984, 2902, 2250, 1688, 1491,1446, 1358, 1250, 1038, 731. LR-MS: 426.1 M+Na⁺; HR-MS (ESI) calculatedfor C₁₈H₁₇N₃O₄S₂Na: 426.0558, found: 426.0555. The constitution andrelative configuration of this product was confirmed by single-crystalX-ray analysis.

Rac-(3R,6S,7S,8aR)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

Minor ETP stereoisomer. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.80 (1H, d,J=8.0 Hz), 6.60 (1H, d, J=8.0 Hz), 6.55 (1H, s), 5.99 (2H, s), 5.03 (1H,s), 3.80 (1H, d, J=15.0 Hz), 3.12 (3H, s), 2.51 (1H, d, J=15.0 Hz), 1.99(3H, s), 1.94 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.3 (C), 162.4(C), 148.6 (C), 148.5 (C), 129.4 (C), 120.1 (CH), 119.6 (C), 108.9 (CH),106.3 (CH), 101.6 (CH₂), 73.8 (C), 73.7 (C), 71.6 (CH), 43.8 (C), 42.3(CH₂), 27.9 (CH₃), 27.2 (CH₃), 18.3 (CH₃). IR (film): v/cm⁻¹ 2988, 2940,2900, 2249, 1694, 1504, 1448, 1355, 1248, 1111, 1038, 912, 731. LR-MS:426.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H₁₇N₃O₄S₂Na: 426.0558, found:426.0553.

Rac-(3S,6R,7S,8aS)-6-(5-Bromo-2-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.50 (1H, s), 7.45 (1H, dd, J=2.0, 8.5Hz), 6.83 (1H, d, J=8.5 Hz), 5.49 (1H, s), 3.90 (3H, s), 3.45 (1H, d,J=14.5 Hz), 3.10 (3H, s), 2.91 (1H, d, J=14.5 Hz), 1.98 (3H, s), 1.65(3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C), 162.7 (C), 155.8(C), 133.2 (CH), 129.9 (CH), 120.0 (C), 113.4 (C), 112.5 (CH), 73.7 (C),73.3 (C), 65.5 (CH), 55.6 (CH₃), 43.5 (C), 41.9 (CH₂), 27.9 (CH₃), 25.7(CH₃), 18.3 (CH₃). IR (film): v/cm⁻¹ 2937, 2359, 1692, 1488, 1359, 1252,729. LR-MS: 490.0 (M+Na); HR-MS (ESI) calculated for C₁₈H₁₈N₃O₃BrS₂Na:489.9871, found: 489.9862.

Rac-(3S,6R,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(thiophen-2-yl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.36 (1H, d, J=4.5 Hz), 7.30 (1H, br. s),7.07 (1H, t, J=4.5 Hz), 5.30 (1H, s), 3.43 (1H, d, J=14.5 Hz), 3.00-3.15(4H, m), 1.96 (3H, s), 1.66 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm165.5 (C), 162.2 (C), 136.2 (C), 127.7 (CH), 127.6 (CH), 126.8 (CH),119.6 (C), 73.4 (C), 72.9 (C), 67.3 (CH), 44.3 (C), 42.0 (CH₂), 27.9(CH₃), 25.2 (CH₃), 18.2 (CH₃). IR (film): v/cm−¹ 2917, 2361, 1699, 1403,1360, 1251, 1068, 848. LR-MS: 388.1 (M+Na⁺); HR-MS (ESI) calculated forC₁₅H₁₅N₃O₂S₃Na: 388.0224, found: 388.0221.

Rac-(3S,6S,7S,8aS)-6-([1,1′-Biphenyl]-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.72 (2H, d, J=8.5 Hz), 7.66 (2H, d,J=8.5 Hz), 7.45-7.53 (4H, m), 7.41 (1H, t, J=7.5 Hz), 5.02 (1H, s), 3.41(1H, d, J=15.0 Hz), 3.16 (3H, s), 3.09 (1H, d, J=15.0 Hz), 2.02 (3H, s),1.78 (3H, s); C-NMR (125 MHz, CDCl₃): δ/ppm 165.6 (C), 162.2 (C), 142.3(C), 140.4 (C), 132.6 (C), 128.8 (2CH), 127.7 (2CH), 127.6 (2CH), 127.2(CH+2CH), 120.2 (C), 73.5 (C), 73.4 (C), 72.2 (CH), 44.4 (C), 42.9(CH₂), 27.8 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2935, 2250,1689, 1488, 1448, 1414, 1358, 1252, 910. LR-MS: 458.2 (M+Na⁺); HR-MS(ESI) calculated for C₂₃H₂₁N₃O₂S₂Na: 458.0973, found: 458.0972.

Rac-(3S,6S,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(p-tolyl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.28-7.35 (4H, m), 4.94 (1H, s), 3.37(1H, d, J=15.0 Hz), 3.14 (3H, s), 3.06 (1H, d, J=15.0 Hz), 2.43 (3H, s),2.00 (3H, s), 1.74 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C),162.1 (C), 139.3 (C), 130.7 (C), 129.7 (2CH), 126.7 (2CH), 120.3 (C),73.5 (C), 73.3 (C), 72.4 (CH), 44.5 (C), 42.9 (CH₂), 27.8 (CH₃), 24.7(CH₃), 21.4 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2990, 2921, 2245, 1685,1516, 1358, 1253, 816. LR-MS: 396.2 (M+Na⁺); HR-MS (ESI) calculated forC₁₈H₁₉N₃O₂S₂Na: 396.0816, found: 396.0800. The constitution and relativeconfiguration of this product was confirmed by single-crystal X-rayanalysis.

Rac-(3S,6S,7S,8aS)-6-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.90-7.00 (3H, m), 4.88 (1H, s), 4.32(4H, m), 3.36 (1H, d, J=14.5 Hz), 3.14 (3H, s), 3.05 (1H, d, J=14.5 Hz),2.00 (3H, s), 1.72 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C),162.2 (C), 144.4 (C), 143.7 (C), 126.9 (C), 120.2 (C), 119.9 (CH), 117.9(CH), 115.9 (CH), 73.4 (C), 73.3 (C), 72.0 (CH), 64.3 (2CH₂), 44.4 (C),42.7 (CH₂), 27.8 (CH₃), 24.9 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2984,2938, 2251, 1690, 1592, 1509, 1360, 1288, 1260, 1067, 912. LR-MS: 439.9(M+Na⁺); HR-MS (ESI) calculated for C₁₉H₁₉N₃O₄S₂Na: 440.0715, found:440.0728.

Rac-(3S,6S,7S,8aS)-6-(4-Chlorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.42 (2H, d, J=8.5 Hz), 7.32 (2H, d,J=8.5 Hz), 4.87 (1H, s), 3.32 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.99(1H, d, J=15.0 Hz), 1.94 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.5 (C), 162.1 (C), 135.5 (C), 132.2 (C), 129.3 (2CH),128.2 (2CH), 120.0 (C), 73.5 (C), 73.4 (C), 71.8 (CH), 44.3 (C), 42.9(CH₂), 27.8 (CH₃), 24.7 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2992, 2941,2246, 1690, 1493, 1359, 1255, 1090, 825. LR-MS: 416.2 (M+Na⁺); HR-MS(ESI) calculated for C₁₇H₁₆N₃O₂ClS₂Na: 416.0270, found: 416.0261.

Rac-(3S,6S,7S,8aS)-6-(3,4-Dichlorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.53 (1H, d, J=8.0 Hz), 7.46 (1H, s),7.25 (1H, d, J=8.0 Hz), 4.85 (1H, s), 3.33 (1H, d, J=15.0 Hz), 3.09 (3H,s), 3.00 (1H, d, J=15.0 Hz), 1.95 (3H, s), 1.70 (3H, s); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 165.4 (C), 162.0 (C), 133.9 (2C), 133.2 (C), 131.2(CH), 129.0 (CH), 126.2 (CH), 119.8 (C), 73.4 (2C), 71.2 (CH), 44.2 (C),42.9 (CH₂), 27.9 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹ 2936,2250, 1696, 1472, 1359, 1252, 1136, 1031, 912, 730. LR-MS: 449.9(M+Na⁺); HR-MS (ESI) calculated for C₁₇H₁₅N₃O₂Cl₂S₂Na: 449.9880, found:449.9853.

Rac-(3S,6R,7S,8aS)-6-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, s), 7.05 (1H, s), 6.02 (2H, s),5.22 (1H, s), 3.41 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.98 (1H, d, J=15.0Hz), 1.95 (3H, s), 1.75 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5(C), 162.2 (C), 149.1 (C), 148.3 (C), 126.8 (C), 120.0 (C), 114.4 (C),113.2 (CH), 108.0 (CH), 102.3 (CH₂), 73.6 (C), 73.3 (C), 71.0 (CH), 44.2(C), 42.8 (CH₂), 27.8 (CH₃), 25.5 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹3043, 2986, 2913, 2243, 1694, 1504, 1480, 1355, 1242, 1118, 1037, 931,734. LR-MS: 504.1 (M+Na⁺); HR-MS (ESI) calculated for C₁₈H₁₆N₃O₄BrS₂Na:503.9663, found: 503.9647.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-((dimethylamino)methyl)-2,3,7-trimethyl-tetrahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4-dione

Prepared fromrac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]-pyrazine-7-carbonitrileby conventional NiCl₂/NaBH₄ reduction of the nitrile, Eschweiler-Clarkedimethylation of the resulting primary amine and sulfidation.

H-NMR (500 MHz, CDCl₃): δ/ppm 6.91 (1H, s), 6.76-6.83 (2H, m), 5.97 (2H,s), 4.77 (1H, s), 3.18 (1H, d, J=14.5 Hz), 3.07 (3H, s), 2.55 (1H, d,J=14.5 Hz), 2.15 (6H, s), 1.97 (2H, s), 1.94 (3H, s), 1.27 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.6 (C), 163.1 (C), 148.0 (C), 147.3(C), 130.0 (C), 121.3 (CH), 108.4 (CH), 108.1 (CH), 101.3 (CH₂), 74.9(C), 74.2 (CH), 73.5 (C), 66.1 (CH₂), 8.2 (2CH₃), 47.8 (C), 41.8 (CH₂),27.7 (CH₃), 26.5 (CH₃), 18.4 (CH₃). IR (film): v/cm⁻¹ 2940, 2821, 2770,1690, 1490, 1445, 1379, 1353, 1249, 1104, 1038, 932, 734. LR-MS: 458.2(M+Na⁺); HR-MS (ESI) calculated for C₂₀H₂₅N₃O₄S₂Na: 458.1184, found:458.1185.

Rac-(3S,6R,7S,8aS)-6-(4-Methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.52-6.62 (2H, m), 6.01 (2H, s), 4.84(1H, s), 3.89 (3H, s), 3.31 (1H, d, J=15.0 Hz), 3.09 (3H, s), 3.01 (1H,d, J=15.0 Hz), 1.96 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 165.5 (C), 162.0 (C), 149.2 (C), 143.8 (C), 136.0 (C), 128.1 (C),120.2 (C), 106.1 (CH), 102.1 (CH₂), 101.2 (CH), 73.6 (C), 73.5 (C), 72.4(CH), 56.6 (CH₃), 44.5 (C), 42.7 (CH₂), 27.9 (CH₃), 25.1 (CH₃), 18.2(CH₃). IR (film): v/cm⁻¹ 2940, 2902, 2241, 1696, 1636, 1513, 1453, 1358,1250, 1201, 1130, 1093, 1044, 874, 734. LR-MS: 456.0 M+Na⁺; HR-MS (ESI)calculated for C₁₉H₁₉N₃O₅S₂Na: 456.0664, found: 456.0653.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(methoxymethyl)-2,3-dimethyl-1,4-dioxohexa-hydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.91 (1H, s), 6.80-6.88 (2H, m), 5.99(2H, s), 5.26 (1H, s), 3.61 (1H, d, J=9.5 Hz), 3.58 (1H, d, J=15.0 Hz),3.54 (1H, d, J=9.5 Hz), 3.47 (3H, s), 3.08 (3H, s), 2.88 (1H, d, J=15.0Hz), 1.94 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5 (C), 162.0 (C),148.4 (C), 148.3 (C), 128.0 (C), 120.9 (CH), 118.4 (C), 108.7 (CH),107.4 (CH), 101.5 (CH₂), 73.8 (C), 73.5 (C), 73.0 (CH₂), 67.2 (CH), 59.7(CH₃), 49.6 (C), 38.5 (CH₂), 27.8 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹2993, 2928, 2898, 2250, 1693, 1497, 1491, 1447, 1358, 1250, 1118, 1038,914, 731. LR-MS: 456.0 M+Na⁺; HR-MS (ESI) calculated for C₁₉H₁₉N₃O₅S₂Na:456.0664, found: 456.0650.

Rac-(3S,6S,7S,8aS)-6-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.09-7.15 (3H, m), 4.89 (1H, s), 3.33(1H, d, J=14.5 Hz), 3.08 (3H, s), 3.00 (1H, d, J=14.5 Hz), 1.95 (3H, s),1.69 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.4 (C), 162.1 (C),144.4 (C), 144.2 (C), 131.7 (C, t, J=255 Hz), 130.0 (C), 122.6 (CH),119.9 (C), 109.8 (CH), 108.3 (CH), 77.3 (C), 73.4 (C), 72.0 (CH), 44.4(C), 42.9 (CH₂), 27.9 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): v/cm⁻¹2986, 2942, 2253, 1697, 1501, 1450, 1358, 1240, 1154, 1034, 903, 731.LR-MS: 462.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H₁₅N₃O₄F₂S₂Na:462.0370, found: 462.0377.

Rac-(3R,6R,7S,8aR)-6-(5-Bromobenzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.13 (1H, d, J=8.5 Hz), 6.69 (1H, d,J=8.5 Hz), 5.90 (1H, s), 5.80 (1H, s), 5.65 (1H, s), 3.88 (1H, d, J=15.5Hz), 3.06 (3H, s), 2.57 (1H, d, J=15.5 Hz), 2.12 (3H, s), 1.95 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5 (C), 161.6 (C), 147.6 (C), 145.1(C), 126.4 (CH), 119.6 (C), 117.7 (C), 114.9 (C), 110.5 (CH), 102.1(CH₂), 74.6 (C), 73.7 (C), 68.5 (CH), 44.3 (CH₂), 43.1 (C), 27.6 (CH₃),27.5 (CH₃), 18.3 (CH₃). IR (film): v/cm⁻¹ 2986, 2880, 2250, 1695, 1457,1357, 1242, 1059, 1035, 932, 731. LR-MS: 503.9 M+Na⁺; HR-MS (ESI)calculated for C₁₈H₁₆N₃O₄S₂BrNa: 503.9663, found: 503.9655. Theconstitution and relative configuration of this product was confirmed bysingle-crystal X-ray analysis.

Rac-(3S,6R,7S,8aS)-6-(Benzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.80-6.96 (3H, m), 6.02 (1H, s), 6.00(1H, s), 5.22 (1H, s), 3.35 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.98 (1H,d, J=15.0 Hz), 1.95 (3H, s), 1.70 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 165.6 (C), 162.2 (C), 147.6 (C), 145.2 (C), 122.3 (CH), 120.1 (C),119.5 (CH), 115.7 (C), 109.5 (CH), 101.3 (CH₂), 73.6 (C), 73.3 (C), 66.2(CH), 44.1 (C), 42.7 (CH₂), 27.8 (CH₃), 25.1 (CH₃), 18.2 (CH₃). IR(film): v/cm⁻¹ 12991, 2905, 2241, 1697, 1462, 1357, 1249, 1063, 1029,931, 731. LR-MS: 426.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H₁₇N₃O₄S₂Na:426.0558, found: 426.0552. The constitution and relative configurationof this product was confirmed by single-crystal X-ray analysis.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3-dimethyl-7-(morpholinomethyl)-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.96 (1H, s), 6.91 (1H, d, J=8.0 Hz),6.84 (1H, d, J=7.0 Hz), 5.99 (2H, s), 5.17 (1H, s), 3.65-3.74 (4H, m),3.56 (1H, d, J=14.5 Hz), 3.04 (3H, s), 2.92 (1H, d, J=14.5 Hz),2.70-2.80 (2H, m), 2.60-2.75 (4H, m), 1.94 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.6 (C), 162.2 (C), 148.4 (C), 148.3 (C), 128.2 (C),121.1 (CH), 119.7 (C), 108.7 (CH), 107.6 (CH), 101.5 (CH₂), 73.7 (C),73.5 (C), 68.7 (CH), 67.1 (2CH₂), 63.4 (CH₂), 55.3 (2CH₂), 49.6 (C),39.5 (CH₂), 27.9 (CH₃), 18.2 (CH₃). IR (film): v/cm⁻¹ 2958, 2855, 2816,2248, 1688, 1491, 1447, 1356, 1260, 1116, 1037, 914, 864, 730. LR-MS:511.1 M+Na⁺; HR-MS (ESI) calculated for C₂₂H₂₄N₄O₅S₂Na: 511.1086, found:511.1068.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-butyl-3,7-dimethyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.88 (1H, s), 6.82 (2H, app. s), 5.99(2H, s), 4.81 (1H, s), 3.78, (1H, m),3.30 (1H, d, J=14.5 Hz), 2.99 (1H,d, J=14.5 Hz), 1.98 (3H, s), 1.66 (3H, s), 1.62 (2H, m), 1.38 (2H, m),0.96 (3H, t, J=7.2 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.2 (C), 162.4(C), 148.7 (C), 148.4 (C), 127.7 (C), 120.8 (CH), 120.5 (C), 108.7 (CH),107.4 (CH), 101.7 (CH₂), 73.8 (C), 73.0 (C), 72.5 (CH), 44.6 (C), 43.3(CH₂), 43.0 (CH₂), 29.9 (CH₂), 25.0 (CH₃), 24.8 (CH₂), 20.4 (CH₂), 17.8(CH₃), 14.0 (CH₃). IR (film): v/cm⁻¹ 2984, 2902, 2250, 1688, 1491, 1446,1358, 1250, 1038, 731. HR-MS (ESI) calculated for C₂₁H₂₃N₃O₄S₂Na:468.1022, found: 468.1018.

Rac-(3S,6S,7S,8aS)-6-(4-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.30 (2H, d, J=8.5 Hz), 6.96 (2H, d,J=8.5 Hz), 4.85 (1H, s), 3.79 (3H, s), 3.28 (1H, d, J=15.0 Hz), 3.08(3H, s), 2.99 (1H, d, J=15.0 Hz), 1.94 (3H, s), 1.66 (3H, s); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 165.0 (C), 162.3 (C), 159.9 (C), 128.7 (C),127.3 (2CH), 117.8 (C), 114.7 (2CH), 73.6 (C), 73.4 (C), 72.0 (CH), 55.2(CH₃), 44.2 (C), 42.7 (CH₂), 27.7 (CH₃), 24.8 (CH₃), 18.0 (CH₃). IR(film): v/cm¹ 2988, 2940, 2246, 1690, 1493, 1359, 1255, 1093, 756. HR-MS(ESI) calculated for C₁₈H₁₉N₃O₃S₂Na: 412.0760, found: 412.0753.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-benzyl-2,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.33-7.31 (m, 2H), 7.29-7.24 (m, 3H), 6.86 (s,1H), 6.82-6.81 (m, 2H), 5.99-5.98 (m, 2H), 4.90 (s, 1H), 3.82 (d, J=15.3Hz, 1H), 3.75 (d, J=15.3 Hz, 1H), 3.32 (d, J=14.9 Hz, 1H), 3.07 (s, 3H),3.02 (d, J=14.9 Hz, 1H), 1.70 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ166.4 (C), 161.4 (C), 148.6 (C), 148.3 (C), 133.6 (C), 129.9 (CH), 128.7(CH), 127.8 (CH), 127.4 (C), 120.8 (CH), 120.3 (C), 108.7 (CH), 107.4(CH), 101.6 (CH₂), 77.8 (C), 73.5 (C), 72.7 (CH), 44.5 (C), 42.9 (CH₂),36.6 (CH₂), 29.4 (CH₃), 25.0 (CH₃) ppm; IR (film) v/cm⁻¹ 2917, 1695,1491, 1447, 1357, 1249, 1190, 1037, 931, 817 cm⁻¹; HRMS (ESI) calcd forC₂₄H₂₁N₃O₄S₂Na⁺ (M+Na) 502.0871, found 502.0867.

Rac-(3S,6S,7S,8aS)-2-allyl-6-(benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.88 (s, 1H), 6.84 (app. s, 2H), 5.99 (s, 2H),5.89-5.82 (m, 1H), 5.28 (d, J=17.6 Hz, 1H), 5.25 (d, J=10.6 Hz, 1H),4.83 (s, 1H), 4.41-4.37 (m, 1H), 4.02 (dd, J=16.2, 5.6 Hz 1H), 3.30 (d,J=14.9 Hz, 1H), 3.01 (d, J=14.9 Hz, 1H), 1.98 (s, 3H), 1.66 (s, 3H) ppm;¹³C-NMR (126 MHz, CDCl₃) δ 165.1 (C), 162.2 (C), 148.6 (C), 148.3 (C),131.5 (CH), 127.6 (C), 120.7 (CH), 120.4 (C), 118.4 (CH₂), 108.6 (CH),107.2 (CH), 101.6 (CH₂), 73.6 (C), 73.1 (C), 72.4 (CH), 45.2 (CH₂), 44.5(C), 42.9 (CH₂), 24.8 (CH₃), 17.5 (CH₃) ppm; IR (film) v/cm⁻¹ 1688,1491, 1446, 1359, 1249, 1191, 1103, 1038, 929 cm⁻¹; HRMS (ESI) calcd forC₂₀H₁₉N₃O₄S₂Na+(M+Na) 452.0715, found 452.0719.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-3,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.87 (s, 1H), 6.84-6.81 (app. s, 2H), 5.99 (s,2H), 4.80 (s, 1H), 3.27 (d, J=14.9 Hz, 1H), 2.93 (d, J=14.9 Hz, 1H),2.57-2.53 (m, 1H), 2.12 (s, 3H), 1.66 (s, 3H), 1.29-1.24 (m, 1H),1.06-0.97 (m, 2H), 0.96-0.90 (m, 1H) ppm; 13C-NMR (126 MHz, CDCl₃) δ165.7 (C), 162.3 (C), 148.6 (C), 148.3 (C), 127.6 (C), 120.7 (CH), 120.4(C), 108.6 (CH), 107.2 (CH), 101.6 (CH₂), 74.4 (C), 74.1 (C), 72.4 (CH),44.5 (C), 42.9 (CH₂), 25.8 (CH), 24.8 (CH₃), 17.8 (CH₃), 8.2 (CH₂), 7.7(CH₂) ppm; IR (film) v/cm⁻¹ 1696, 1491, 1446, 1348, 1248, 1189, 1037,930, 735 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₉N₃O₄S₂Na⁺ (M+Na) 452.0715,found 452.0702.

Rac-(3S,6S,7S,8aS)-6-(3,4-bis(allyloxy)phenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.95 (s, 1H), 6.92-6.88 (m, 2H), 6.11-6.03 (m,2H), 5.45-5.38 (m, 2H), 5.29-5.24 (m, 2H), 4.87 (s, 1H), 4.63-4.60 (m,4H), 3.31 (d, J=14.8 Hz, 1H), 3.08 (s, 3H), 2.98 (d, J=14.8 Hz, 1H),1.95 (s, 3H), 1.66 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ165.6 (C),162.2 (C), 149.3 (C), 148.8 (C), 133.4 (CH), 133.3 (CH), 126.5 (C),120.3 (CH), 119.8, 117.9 (CH₂), 117.8 (CH₂), 113.7 (CH), 112.2 (CH),73.8 (C), 73.6 (C), 72.4 (C), 70.0 (CH₂), 69.9 (CH₂), 44.5 (C), 42.8(CH₂), 27.9 (CH₃), 25.1 (CH₃), 18.3 (CH₃) ppm; IR (film) v/cm⁻¹ 1695,1607, 1593, 1516, 1424, 1380, 1360, 1262, 1218, 1141, 996, 919, 731cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₅N₃O₄S₂Na⁺ (M+Na) 494.1184, found494.1188.

Rac-(3S,6S,7S,8aS)-6-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexa-hydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.60 (s, 1H), 6.58 (s, 1H), 6.00 (m, 2H), 4.84(s, 1H), 3.89 (s, 3H), 3.31 (d, J=14.8 Hz, 1H), 3.08 (s, 3H), 2.99 (d,J=14.8 Hz, 1H), 1.95 (s, 3H), 1.67 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 165.5 (C), 162.1 (C), 149.3 (C), 143.9 (C), 136.1 (C), 128.2 (C),120.2 (C), 106.5 (CH), 102.0 (CH₂), 101.3 (CH), 73.7 (C), 73.6 (C), 72.5(CH₂), 56.7 (CH₃), 44.5 (C), 42.8 (CH₂), 27.9 (CH₃), 25.2 (CH₃), 18.2(CH₃) ppm; IR (film) v/cm⁻¹ 2984, 2250, 1696, 1637, 1512, 1453, 1358,1246, 1201, 1129, 1093, 1044, 913, 731 cm⁻¹; HRMS (ESI) calcd forC₁₉H₁₉N₃O₅S₂Na⁺ (M+Na) 456.0664, found 456.0648.

Rac-(3S,6S,7S,8aS)-6-(2,3-dihydro-1H-inden-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.26 (d, J=7.2 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=7.2 Hz, 1H), 4.87 (s, 1H), 3.30 (d, J=14.9 Hz, 1H), 3.07 (s, 3H), 3.00(d, J=14.9 Hz, 1H), 2.94-2.89 (m, 4H), 2.08 (app. quintet, J=7.5 Hz,2H), 1.93 (s, 3H), 1.67 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 165.8(C), 162.2 (C), 145.8 (C), 145.0 (C), 131.5 (C), 124.9 (CH), 124.8 (CH),122.9 (CH), 120.5 (C), 73.6 (C), 73.4 (C), 72.8 (CH), 44.6 (C), 43.0(CH₂), 33.0 (CH₂), 32.8 (CH₂), 27.9 (CH₃), 25.4 (CH₂), 24.8 (CH₃), 18.2(CH₃) ppm; IR (film) v/cm⁻¹ 2941, 2251, 1696, 1440, 1359, 1254, 1202,1145, 1112, 1067, 1030, 911, 731 cm⁻¹; HRMS (ESI) calcd forC₂₀H₂₁N₃O₂S₂Na⁺ (M+Na) 422.0973, found 422.0965.

Rac-(3S,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(1-(phenylsulfonyl)-1H-indol-3-yl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 1H), 7.86-7.84 (m, 3H),7.55 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.8 Hz, 2H),7.34 (t, J=7.7 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 5.29 (s, 1H), 3.43 (d,J=14.7 Hz, 1H), 3.10 (s, 3H), 3.05 (d, J=14.7 Hz, 1H), 1.96 (s, 3H),1.70 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ165.5 (C), 162.0 (C), 137.8(C), 135.3 (C), 134.2 (CH), 129.4 (CH), 128.9 (C), 127.1 (CH), 125.8(CH), 125.5 (CH), 123.8 (CH), 120.1 (C), 119.5 (CH), 116.6 (C), 114.1(CH), 73.6 (C), 73.3 (C), 64.2 (CH), 43.8 (C), 42.8 (CH₂), 28.0 (CH₃),25.2 (CH₃), 18.3 (CH₃) ppm; IR (film) v/cm⁻¹ 2360, 1696, 1447, 1361,1214, 1176, 1120, 1095, 974, 747, 725, 684 cm⁻¹; HRMS (ESI) calcd forC₂₅H₂₂N₄O₄S₃Na⁺ (M+Na) 561.0701, found 561.0703.

Example 6

Separation of Enantiomers of ETP Products.

Isolation of (3S,6S,7S,8aS)- and(3R,6R,7R,8aR)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitriles

The two enantiomers were separated by preparative chiral HPLC(stationary phase: CHIRALPAK IA (250×50 mm i.d., 5 micron), mobilephase: reagent alcohol 100%), flow rate 2.5 mL/min). The enantiomericexcess was determined by means of analytical chiral HPLC (stationaryphase CHIRALPAK IA-3 (50×4.6 mm i.d., 3 micron), mobile phase: reagentalcohol 100%, flow rate 1 mL/min, 254 nm): (3S,6S,7S,8aS)-enantiomer:t_(ret)=1.40 min; (3R,6R,7R,8aR)-enantiomer: t_(ret)=2.11 min.

Absolute configuration was assigned on the basis of CD data and existingprecedent [Carmack, M.; Neubert, L. A. J Am. Chem. Soc. 1967, 89,7134-7136. Hauser, D.; Weber, H. P.; Sigg, H. P. Helv. Chim. Acta 1970,53, 1061-1073. Minato, H.; Matsumoto, M.; Katayama, T. J. Chem. Soc. D.1971, 44-45. Nagarajan, R.; Woody, R. W. J. Am. Chem. Soc. 1973, 95,7212-7222. Woody, R. W. Tetrahedron 1973, 29, 1273-1283].

Example 7

Cell Viability Assay of Compound (1) against CTCL

Compound (1) and FK-228 (an anticancer agent used in CTCL) were testedin a cell viability assay using HUT78 cells in a CELLTITER-GLO® assay.An IC₅₀ value of 6.61 nM was determined for compound (1). See, FIG. 1B.An IC₅₀ value of 6.95 nM was determined for FK-228. See FIG. 1C.Analysis of the results demonstrates that the compound (1) has potentantitumor activities against CTCL.

Example 8

Carboxy-Fluorescein Succinimidyl Ester (CFSE) Staining CellProliferation Assay

Compound (1) was tested in a carboxy-fluorescein succinimidyl ester(CFSE) stained HUT78 CTCL proliferation assay. HUT78 cells were stainedwith CFSE dye. The CFSE stained cells were plated into 96-well plates ingrowth medium. The resulted cells were treated with 1.0, 10, or 100 nMsolution of compound (1), and then incubated for 72 h under the growthconditions. After, optical densities were read on a multiwell scanningspectrophotometer at wavelength 488 nm. Cells cultured in the absence ofcompound (1) served as a control. Analysis of the results demonstratesthat the compound (1) inhibits proliferation of HUT78 CTCL cells (seeFIG. 2).

Example 9

Effects of Compound (1) on HUT78 CTCL cells

Compound (1) was tested in a cell proliferation assay using HUT78 CTCLcells. The cells were treated with 0.3, 1, 3, 10, 30, or 100 nMconcentration of compound (1), and then incubated for 48 h or 72 h underthe growth conditions. An IC₅₀ value of 75.00 nM was determined when thecells were incubated in the growth media for 48 h. An IC₅₀ value of10.04 nM was determined when the cells were incubated in the growthmedia for 72 h. Cells cultured in the absence of compound (1) served asa control. Analysis of the results demonstrates that the compound (1)inhibits proliferation of HUT78 CTCL cells in a dose- and time-dependentmanner (see FIG. 3)

Example 10

Induction of Apoptosis by Compound (1)

Compound (1) was tested in a cell apoptosis assay using HUT78 CTCLcells. The cells were treated with 1, 3, 10, or 100 nM concentration ofcompound (1), and then incubated for 72 h under the growth conditions.An IC₅₀ value of 19.71 nM was determined after the cells were incubatedin the growth media for 72 h. Cells cultured in the absence of compound(1) served as a control. Analysis of the results demonstrates that thecompound (1) induces apoptosis of HUT78 CTCL cells in a dose-dependentmanner (see FIG. 4).

Example 11

Tumor Volume, Size, and Weight Comparison in Compound (1) Regimen VersusFK-228 Regimen in HUT78 CTCL Mouse Xenograft Model

Compound (1) and FK-228 were tested for tumor growth inhibition in CTCLmouse xenograft models. One group of mice was treated with 20 mg/kg ofcompound (1) using gavage during 3 consecutive days, followed by 3consecutive days of break. Another group of mice was treated with 2mg/kg of FK-228 intraperitoneal, twice weekly. Mice with no treatmentserved as a control. The tumor volume, size, and weight were compared 12days after the treatments started. Analysis of the results demonstratesthat compound (1) regimen (squares) results in tumor growth inhibition,compared to the FK-228 regimen (triangles), and to the vehicle (circles)(FIG. 5). Compound (1) regimen also results in the reduction of thetumor size (FIG. 6).

Ascites and diarrhea in mice were observed in romidespin regimen,suggesting drug associated toxicity, while no toxicity was observed incompound (1) regimen. The tumor weight inhibition in a HUT78 CTCL mousexenograft model was 89.8% in compound (1) regimen (P<0.001), suggestingcompound (1) exhibited significantly more potent in vivo efficacy thanromidepsin (FIG. 7).

Example 12

Phase 1/2 Study to Evaluate Safety of Compound 1 in Subjects withCutaneous T-Cell Lymphoma (CTCL)

The primary objective of this study is to characterize the safety,tolerability, and dose-limiting toxicities (DLTs) of compound (1) whenadministered orally to patients with CTCL that has relapsed (returnedafter responding to previous treatment) or is refractory (has notresponded to previous treatment).

Study Objectives

-   -   The safety and tolerability of multiple doses of compound (1);    -   The effect of multiple doses of compound (1) on relapsed CTCL;        and    -   The effect of multiple doses of compound (1) on refractory CTCL.

Patients: Eligible subjects will be men and women 18 years and old.Healthy volunteers are not eligible.

Inclusion Criteria:

-   -   Histologically confirmed diagnosis of CTCL including:        -   a. Mycosis fungoides        -   b. Sézary syndrome        -   c. Primary cutaneous anaplastic large cell    -   Stage Ib to IVb disease    -   Progression of disease (PD) or relapse of disease after at least        1 previous systemic therapy, PD after last prior treatment        regimen, and recovered from the toxic effects of prior therapy    -   Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2    -   Age >18 years, of either sex    -   Life expectancy >3 months    -   Adequate blood, liver, and kidney function as determined by        laboratory tests    -   Female patients with childbearing potential must be using a        hormonal contraceptive, intra uterine device, diaphragm with        spermicide, or condom with spermicide for the duration of the        study. Women of childbearing potential must have a negative        serum or urinary hCG pregnancy test    -   Male patients, who are not surgically sterile, must use a condom        with spermicide for the duration of the study    -   Have given written informed consent, prior to any study related        procedure not part of the patient's normal medical care, with        the understanding that consent may be withdrawn by the patient        at any time without prejudice to future medical care

Exclusion Criteria:

-   -   Active concurrent malignancy (except non-melanoma skin cancer or        carcinoma in situ of the cervix). If there is a history of prior        malignancy, the patient must be disease-free for ≥5 years.        Patients with other prior malignancies <5 years before study        entry may be enrolled if treatment resulted in complete        resolution of the cancer and currently have no clinical,        radiologic, or laboratory evidence of active or recurrent        disease    -   Have participated in any other investigational study or received        an experimental therapeutic procedure considered to interfere        with the study in the 2 months preceding this study    -   Human immunodeficiency virus (HIV)-positive diagnosis with a CD4        count of <100 mm3 or detectable viral load within the past 3        months, and is receiving combination anti-retroviral therapy    -   Have had PUVA, topical nitrogen mustard, spot or total skin        electron beam therapy, oral retinoids, or any, immunotherapy        (e.g. interferon-α, denileukin difitox, alemtuzumab) or        chemotherapy regimen within 2 weeks of this study. Patients must        have recovered from all acute toxicities    -   Evidence of CNS lymphoma    -   Active uncontrolled infection, underlying medical condition that        would impair ability to receive protocol treatment    -   Uncontrolled medical conditions, requiring surgical or        pharmacological treatment (exceptions must be approved by the        Study Director)    -   Serious concomitant disease (e.g. significant cardiac disease)        are not eligible    -   Primary or acquired thrombocytopenia    -   Inadequate bone marrow reserve: WBC <3.5×10{circumflex over        ( )}9/L, neutrophils <1.0×10{circumflex over ( )}9/L,        thrombocytes <100×10{circumflex over ( )}9/L, Hb<8.5 g/dL or        coagulation abnormalities    -   Inadequate liver function: total bilirubin >1.5×upper limit of        normal values (ULN), AST, ALT, or alkaline phosphatase >2.5×ULN    -   Have inadequate renal function, defined by serum creatinine >250        μmol/L    -   Retinopathy, history of retinal laser surgery, or an ERG <50% of        normal

Study Design:

-   -   Allocation: Non-Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Open Label    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), of compound (1) when administered to subjects        with CTCL. Specifically, this measure will be assessed by number        of subjects experiencing treatment emergent adverse events        indicative of DLT [Time Frame: Assessed at the end of every        even-numbered cycle (every 8 weeks) for the first 6 months, then        every 4 cycles (16 weeks)]

Secondary Outcome Measures:

-   -   The assessment of patient-reported changes of pruritus during        treatment [Time Frame: Monthly]    -   Responses in index lesions assessed by lesion measurements with        photographic supporting documentation [Time Frame: Monthly]    -   Duration of Response (DOR) [Time Frame: Day 1 until disease        progression/recurrence, or up to 12 months (Lead-in) and Day 1        until disease progression/recurrence, or up to 30 months]    -   Time to Response (TTR) [Time Frame: Up to 12 months (Lead-in)        and up to 30 months]    -   Objective Response Rate (ORR) [Time Frame: Day 1 until disease        progression/recurrence, up to 12 months (Lead-in) and Day 1        until disease progression/recurrence, up to 30 months]

Example 13

Synthesis and Characterization Data

Rel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile(2) andRel-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epitrithiopyrrolo[1,2-a]pyrazine-7-carbonitrile(3). A three-neck 250 mL round bottom flask was fitted with an overheadmechanical stirrer with a grease-sealed glass fitting. The flask wascharged with 1 (2.07 g, 6.1 mmol) and S₈ (1.56 g, 6.1 mmol) and fittedwith two rubber septa. The flask was evacuated under vacuum andback-filled with Ar three times. The solids were suspended in anhydrousTHF (60 mL) and the suspension was cooled in an ice bath. After 5 min.,a solution of NaHMDS (0.6 M in PhMe, 60 mL, 36 mmol) was added over 10min with vigorous stirring. The reaction was maintained at 0° C. for 3h. The reaction was quenched with sat. aq. NH₄Cl (50 mL) and H₂O (50mL). The biphasic mixture was extracted with EtOAc (3×150 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Flash chromatography (30×250 mm of SiO₂, 5 to 10%EtOAc in CH₂Cl₂ gradient elution) afforded a 2:1 mixture of 2 and 3 (880mg, ca. 2.12 mmol, 35% yield) as an off-white solid.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)diethanethioate (4, LEO-16-1833). A mixture of 2 and 3 (53 mg, ca. 0.13mmol) was suspended in degassed THF/EtOH (1:1, 1.3 mL) under Ar. Thesuspension was cooled in an ice bath. NaBH₄ (17 mg, 0.44 mmol) was addedin 3 portions over 3 min. After 5 min, the cold bath was removed and thereaction was maintained at room temperature for 1 h. The solvent wasremoved in vacuo. The crude residue was suspended in EtOAc (2.5 mL) andK₂CO₃ (35 mg, 0.25 mmol) was added. Ac₂O (30 μL, 0.32 mmol) was addedand the reaction was maintained for 17 h. The reaction was diluted withH₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.Flash chromatography (12×150 mm of SiO₂, 10% EtOAc in CH₂Cl₂) affordedbis-thioacetate 4 (60 mg, 0.12 mmol, 92% yield) as a colorless solid. ¹HNMR (500 MHz, CDCl₃): δ 6.97 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.84 (d,J=8.1 Hz, 1H), 6.00 (s, 2H), 4.86 (s, 1H), 4.34 (d, J 14.6 Hz, 1H), 3.18(s, 3H), 2.41-2.37 (m, 7H), 2.10 (s, 3H), 1.70 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 191.9 (C), 191.8 (C), 164.9 (C), 162.8 (C), 148.3 (C),148.2 (C), 129.2 (C), 120.9 (C), 120.0 (CH), 108.8 (CH), 106.7 (CH),101.5 (CH₂), 73.6 (C), 73.2 (CH), 72.1 (C), 44.8 (CH₂), 42.4 (C), 31.6(CH₃), 31.5 (CH₃), 31.1 (CH₃), 25.3 (CH₃), 23.4 (CH₃); IR (thin film):3059, 2986, 2919, 1693, 1504, 1492, 1446, 1366, 1252, 1105 cm⁻¹; HRMS(ESI) calculated for C₂₂H₂₃N₃O₆S₂ (M−Na) 512.0926, observed 512.0909.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)dibenzothioate (5, LEO-16-1836). Prepared in analogous fashion tocompound 4 from a mixture of 2 and 3 (51 mg, ca. 0.12 mmol) and benzoylchloride (30 μL, 0.26 mmol). Afforded 5 (48 mg, 0.079 mmol, 66% yield)as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 7.90 (d, J=7.3 Hz, 2H),7.87 (d, J=7.3 Hz, 2H), 7.62 (app t, J=7.4 Hz, 1H), 7.55 (app t, J=7.4Hz, 1H), 7.46 (app t, J 7.7 Hz, 2H), 7.39 (app t, J=7.8 Hz, 2H), 7.01(s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.98 (s, 2H),4.94 (s, 1H), 4.43 (d, J=14.8 Hz, 1H), 3.29 (s, 3H), 2.59 (d, J=14.8 Hz,1H), 2.23 (s, 3H), 1.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 188.35 (C),188.32 (C), 165.1 (C), 163.2 (C), 148.3 (C), 148.2 (C), 137.1 (C), 136.9(C), 134.2 (CH), 134.0 (CH), 129.2 (C), 129.0 (2CH), 128.9 (2CH), 128.0(2CH), 127.8 (2CH), 120.8 (C), 120.0 (CH), 108.8 (CH), 107.0 (CH), 101.5(CH₂), 74.0 (C), 73.4 (CH), 72.0 (C), 45.8 (CH₂), 42.4 (C), 31.4 (CH₃),25.3 (CH₃), 24.2 (CH₃); IR (thin film): 1682, 1491, 1446, 1360, 1251,1200, 1038 cm⁻¹; HRMS (ESI) calculated for C₃₂H₂₇N₃O₆S₂Na (M−Na)636.1239, observed 636.1212.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)bis(2-phenylethanethioate) (6, LEO-16-1835). Prepared in analogousfashion to compound 4 from a mixture of 2 and 3 (53 mg, ca. 0.13 mmol)and phenylacetyl chloride (40 μL, 0.30 mmol). Afforded 6 (59 mg, 0.091mmol, 70% yield) as a colorless foam. ¹H NMR (600 MHz, CDCl₃): δ 7.39(app t, J=7.4 Hz, 2H), 7.34 (app t, J=6.7 Hz, 2H), 7.31-7.25 (m, 6H),6.91 (s, 1H), 6.82-6.79 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.03 (d, J=1.3Hz, 1H), 6.02 (d, J=1.3 Hz, 1H), 4.83 (s, 1H), 4.27 (d, J=14.6 Hz, 1H),3.88 (d, J=16.1 Hz, 1H), 3.82 (d, J=16.1 Hz, 1H), 3.74 (app s, 2H), 3.09(s, 3H), 2.36 (d, J=14.6 Hz, 1H), 2.04 (s, 3H), 1.66 (s, 3H); ¹³C NMR(125 MHz, CDCl₃): δ 193.3 (C), 193.2 (C), 164.9 (C), 162.5 (C), 148.3(C), 148.2 (C), 132.6 (C), 132.3 (C), 130.3 (2CH), 129.9 (2CH), 129.1(C), 129.0 (2CH), 128.7 (2CH), 127.9 (CH), 127.8 (CH), 120.9 (C), 120.0(CH), 108.7 (CH), 106.8 (CH), 101.5 (CH₂), 73.8 (C), 73.1 (CH), 71.8(C), 51.2 (CH₂), 50.9 (CH₂), 44.9 (CH₂), 42.3 (C), 30.9 (CH₃), 25.2(CH₃), 23.3 (CH₃); IR (thin film): 3062, 3030, 2905, 1690, 1492, 1446,1361, 1251, 1038 cm⁻¹; HRMS (ESI) calculated for C₃₄H₃₁N₃O₆S₂Na (M−Na),664.1552, observed 664.1559.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-isocyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)O,O′-dimethyl bis(carbonothioate) (7, LEO-16-1837). Prepared inanalogous fashion to compound 4 from a mixture of 2 and 3 (48 mg, ca.0.12 mmol) and methyl chloroformate (20 μL, 0.26 mmol). Afforded 7 (36mg, 0.070 mmol, 57% yield) as a colorless solid. ¹H NMR (500 MHz,CDCl₃): δ 6.93 (d, J=1.3 Hz, 1H), 6.89 (dd, J=8.0, 1.3 Hz, 1H), 6.82 (d,J=8.0 Hz, 1H), 5.97 (s, 2H), 4.90 (s, 1H), 4.40 (d, J=14.7 Hz, 1H), 3.85(s, 3H), 3.79 (s, 3H), 3.16 (s, 3H), 2.42 (d, J=14.7 Hz, 1H), 2.10 (s,3H), 1.70 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.6 (C), 166.4 (C),165.2 (C), 1862.8 (C), 148.3 (C), 148.2 (C), 129.0 (C), 120.8 (C), 119.9(CH), 108.7 (CH), 106.8 (CH), 101.5 (CH₂), 73.2 (CH), 72.9 (C), 70.9(C), 54.9 (CH₃), 54.8 (CH₃), 45.2 (CH₂), 42.1 (CH), 30.6 (CH₃), 25.3(CH₃), 23.9 (CH₃); IR (thin film): 2954, 1729, 1681, 1493, 1446, 1366,1130 cm⁻¹; HRMS (ESI) calculated for C₂₂H₂₃N₃O₈S₂Na (M−Na) 544.0825,observed 544.0793.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)bis(2-chloroethanethioate) (8, LEO-1840). Disulfide 2 (40 mg, 0.10 mmol)was suspended in degassed THF/EtOH (1:1, 1.0 mL) and cooled in an icebath. Solid NaBH₄ (6.3 mg, 0.17 mmol) was added to the suspension. After5 min, the cold bath was removed and the reaction was maintained for 30min. The solvent was removed in vacuo. The residue was suspended inEtOAc (2 mL) and K₂CO₃ (32 mg, 0.23 mmol) was added. Neat chloroacetylchloride (20 μL, 0.25 mmol) was added and the reaction was maintainedfor 30 min. The solution was diluted with distilled H₂O (5 mL) andextracted with EtOAc (3×10 mL). Combined extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo. Flash chromatography(12×150 mm of SiO₂, 5% to 10% EtOAc in CH₂Cl₂) afforded 8 (20 mg, 0.036mmol, 36% yield) as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 6.93(d, J=1.2 Hz, 1H), 6.87 (dd, J=8.1, 1.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),6.00 (s, 2H), 4.88 (s, 1H), 4.26 (s, 2H), 4.22 (d, J=14.6 Hz, 1H), 4.18(s, 2H), 3.19 (s, 3H), 2.47 (d, J=14.6 Hz, 1H), 2.11 (s, 3H), 1.70 (s,3H); ¹³C NMR (150 MHz, CDCl₃): δ 190.1 (C), 189.4 (C), 164.3 (C), 162.4(C), 148.4 (2C), 128.7 (C), 120.7 (C), 120.0 (CH), 108.9 (CH), 106.7(CH), 101.6 (CH₂), 74.5 (C), 73.4 (CH), 72.5 (C), 48.3 (CH₂), 48.2(CH₂), 45.5 (CH₂), 42.4 (C), 31.3 (CH₃), 25.1 (CH₃), 23.9 (CH₃), missing1C; IR (thin film): 2989, 2939, 2253, 1688, 1365, 1251, 1038, 728 cm⁻¹;HRMS (ESI) calculated for C₂₂H₂₁Cl₂N₃O₆S₂Na (M−Na) 580.0146, observed580.0140.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)O,O′-diphenyl bis(carbonothioate) (9, LEO-16-1841). A mixture of 2 and 3(33 mg, ca. 0.082 mmol) was suspended in degassed THF/EtOH (1:1, 1 mL).The suspension was cooled in an ice bath and NaBH₄ (12.6 mg, 0.33 mmol)was added. After 5 min, the cold bath was removed and the reaction wasmaintained for 1 h. The solvent was removed in vacuo. The crude residuewas suspended in anhydrous THF (1 mL) and cooled in an ice bath. To thecooled suspension neat Et₃N (50 μL, 0.36 mmol) and phenyl chloroformate(30 μL, 0.24 mmol) were added. After 1 h, the reaction was quenched withsat aq. NaHCO₃ (2 mL) and extracted with EtOAc (3×5 mL). Combinedextracts were dried over Na₂SO₄, filtered and concentrated in vacuo.Flash chromatography ((12×150 mm of SiO₂, 2% to 5% EtOAc in CH₂Cl₂)afforded 9 (37 mg, 0.057 mmol, 69% yield) as a colorless solid. ¹H NMR(500 MHz, CDCl₃): δ 7.40 (t, J=7.7 Hz, 4H), 7.32-7.21 (m, 4H), 7.15 (d,J=7.9 Hz, 2H), 7.07 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz,1H), 6.04 (app s, 1H), 6.00 (app s, 1H), 5.00 (s, 1H), 4.49 (d, J=14.8Hz, 1H), 3.27 (s, 3H), 2.48 (d, J=14.8 Hz, 1H), 2.21 (s, 3H), 1.76 (s,3H); ¹³C NMR (125 MHz, CDCl₃): δ 165.3 (C), 165.0 (C), 164.9 (C), 162.5(C), 150.9 (C), 150.8 (C), 148.4 (C), 148.3 (C), 129.64 (2CH), 129.63(2CH), 128.9 (C), 126.7 (CH), 126.6 (CH), 121.5 (2CH), 121.2 (2CH),120.8 (C), 120.1 (CH), 108.8 (CH), 106.8 (CH), 101.5 (CH₂), 73.4 (C),73.3 (CH), 71.5 (C), 45.2(CH₂), 42.2 (C), 30.8 (CH₃), 25.2 (CH₃), 23.9(CH₃); IR (thin film): 2922, 1742, 1688, 1490, 1362, 1252, 1183, 1160,1094, 1076 cm⁻¹; HRMS (ESI) calculated for C₃₂H₂₇N₃O₈S₂Na (M−Na)668.1137, observed 668.1145.

Rel-(4S,7S,8S,9aS)-7-(benzo[d][1,3]dioxol-5-yl)-4,8,11-trimethyl-5,10-dioxo-2-thioxotetrahydro-7H-4,9a-(epiminomethano)pyrrolo[2,1-d][1,3,5]dithiazepine-8-carbonitrile(10, LEO-16-1842). Prepared in analogous fashion to compound 9 from amixture of 2 and 3 (36 mg, ca. 0.089 mmol) and phenylchlorothionoformate (30 μL, 0.22 mmol). Afforded 10 (25 mg, 0.56 mmol,63% yield) as a yellow solid. H NMR (600 MHz, CDCl₃): δ 6.83 (d, J=8.0Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.98 (s, 2H), 4.91 (s,1H), 3.12 (s, 3H), 3.10-3.06 (m, 2H), 1.89 (s, 3H), 1.70 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 214.0 (C), 164.6 (C), 161.4 (C), 148.7 (C),148.5 (C), 127.6 (C), 120.3 (CH), 119.9 (C), 109.0 (CH), 106.8 (CH),101.7 (CH₂), 75.0 (C), 73.6 (CH), 73.1 (C), 45.9 (CH₂), 43.2 (C), 28.7(CH₃), 25.1 (CH₃), 19.9 (CH₃); IR (thin film): 2985, 2940, 2901, 2251,1693, 1504, 1490, 1446, 1367, 1251, 1037 cm⁻¹; HRMS (ESI) calculated forC₉H₁₇N₃O₄S₃Na (M−Na) 470.0279, observed 470.0290.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)bis(dimethylcarbamothioate) (11, LEO-16-1843). Prepared in analogousfashion to compound 9 from a mixture of 2 and 3 (29 mg, ca. 0.072 mmol)and phenyl chlorothionoformate (20 μL, 0.22 mmol). Afforded 11 (13 mg,0.024 mmol, 33% yield) as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ7.05 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 5.97 (apps, 1H), 5.96 (app s, 1H), 4.90 (s, 1H), 4.61 (d, J=14.6 Hz, 1H), 3.21(s, 3H), 2.08-2.94 (m, 12H), 2.37 (d, J=14.6 Hz, 1H), 2.10 (s, 3H), 1.69(s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 165.4 (C), 163.89 (C), 163.88 (C),163.7 (C), 148.1 (C), 148.0 (C), 129.7 (C), 121.0 (C), 120.2 (CH), 108.6(CH), 107.0 (CH), 101.3 (CH₂), 73.5 (C), 73.3 (CH), 71.8 (C), 45.3(CH₂), 42.2 (C), 37.2 (CH₃), 31.0 (2CH₃), 29.8 (2CH₃), 25.4 (CH₃), 24.4(CH₃); IR (thin film): 2933, 2237, 1681, 1359, 1252, 1097, 1036 cm⁻¹;HRMS (ESI) calculated for C₂₄H₂₉N₅O₆S₂Na (M−Na) 570.1457, observed570.1443.

Rel-S,S′-((3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-7-cyano-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)bis(2-methoxyethanethioate) (12, LEO-16-1844). A mixture of 2 and 3 (33mg, ca. 0.080 mmol) was suspended in degassed THF/EtOH (1:1, 1 mL). Thesuspension was cooled in an ice bath and NaBH₄ (12.1 mg, 0.32 mmol) wasadded. After 5 min, the cold bath was removed and the reaction wasmaintained for 1.5 h. The solvent was removed in vacuo. The cruderesidue was suspended in anhydrous THF (1 mL) and cooled in a −78° C.bath. To the cooled suspension neat Et₃N (40 μL, 0.29 mmol) and2-methoxyacetyl chloride (20 μL, 0.22 mmol) were added. After 1 h, thereaction was quenched with sat aq. NaHCO₃ (2 mL) and extracted withEtOAc (3×5 mL). Combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. Flash chromatography (12×150 mm of SiO₂, 2% to 5%EtOAc in CH₂Cl₂) afforded 12 (26 mg, 0.047 mmol, 58% yield) as acolorless solid. ¹H NMR (500 MHz, CDCl₃): δ 6.97 (s, 1H), 6.88 (d, J=8.0Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.98 (S, 2H), 4.88 (S, 1H), 4.34 (d,J=14.7 Hz, 1H), 4.15 (d, J=16.3 Hz, 1H), 4.13-4.01 (m, 3H), 3.54 (s,3H), 3.49 (s, 3H), 3.16 (s, 3H), 2.44 (d, J=14.7 Hz, 1H), 2.09 (s, 3H),1.70 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ 196.18 (C), 196.17 (C), 165.0(C), 162.9 (C), 148.3 (C), 148.2 (C), 129.2 (C), 121.0 (C), 120.0 (CH),108.7 (CH), 106.7 (CH), 101.5 (CH₂), 77.8 (CH₂), 77.7 (CH₂), 73.3 (C),73.1 (CH), 71.1 (C), 60.44 (CH₃), 60.43 (CH₃), 44.9 (CH₂), 42.3 (C),31.0 (CH₂), 25.3 (CH₃), 23.8 (CH₃); IR (thin film): 2992, 2935, 2830,2253, 1693, 1492, 1446, 1364, 1251, 1196, 1123, 1038 cm⁻¹; HRMS (ESI)calculated for C₂₄H₂₇N₃O₈S₂Na (M−Na) 572.1137, observed 572.1130.

EthylRel-(2S,4R,5S)-4-cyano-5-(6-methoxypyridin-3-yl)-4-methylpyrrolidine-2-carboxylate(14) and ethylRel-(2S,4S,5S)-4-cyano-5-(6-methoxypyridin-3-yl)-4-methylpyrrolidine-2-carboxylate(15). A 100 mL round-bottom flask was charged with2-methoxypyridine-5-carbaldehyde (13, 1.33 g, 9.92 mmol) and glycineethyl ester hydrochloride (1.66 g, 11.9 mmol) and MeCN (20 mL). To thesuspension was added Et₃N (1.5 mL, 10.8 mmol) and the mixture wasstirred vigorously for 16 h. The solvent was removed in vacuo and thecrude residue was diluted with H₂O (20 mL) and extracted with CH₂Cl₂(3×20 mL). Combined organic extracts were dried over Na₂SO₄, filteredthrough cotton, and concentrated in vacuo. The crude imine (2.11 g, 9.49mmol, 96% yield) was dissolved in anhydrous THF (16 mL) under Ar. To thesuspension was added LiBr (990 mg, 11.4 mmol) and Et₃N (1.6 mL, 11.5mmol). After 2 min, methacrylonitrile (1.2 mL, 14.3 mmol) was added tothe solution and the reaction was maintained for 16 h. The reaction wasconcentrated in vacuo. The residue was diluted with brine (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried over Na₂SO₄, filtered through cotton, and concentrated in vacuo.Flash chromatography (28×250 mm of SiO₂, 20% to 50% EtOAc in hexanes)afforded pyrrolidine ester 14 (300 mg, 1.04 mmol, 11% yield) as acolorless solid and pyrrolidine ester 15 (1.74 g, 6.01 mmol, 63% yield)as a pale yellow oil. Data for 14: ¹H NMR (600 MHz, CDCl₃): δ 8.24 (d,J=2.5 Hz, 1H), 7.70 (dd, J=8.6, 2.5 Hz, 1H), 6.76 (d, J=8.7 Hz, 1H),4.54 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (app t, J=7.3 Hz, 1H), 3.94(s, 3H), 2.75 (dd, J=13.5, 9.7 Hz, 1H), 2.60 (br s, 1H), 2.25 (dd,J=13.5, 6.1 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.03 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 173.0 (C), 164.5 (C), 145.9 (CH), 137.8 (CH), 125.1 (C),123.8 (C), 110.9 (CH), 67.3 (CH), 61.7 (CH₂), 57.2 (CH), 53.7 (CH₃),41.5 (CH₂), 40.2 (C), 20.5 (CH₃), 14.3 (CH₃); IR (thin film): 3344,2983, 2947, 2904, 2850, 2235, 1737, 1608, 1495, 1285, 1202, 1028 cm⁻¹;HRMS (ESI) calculated for C₁₅H₁₉N₃O₃ (M−Na) 312.1324, observed 312.1316.Data for 15: ¹H NMR (600 MHz, CDCl₃): δ 8.12 (d, J=2.5 Hz, 1H), 7.96(dd, J=8.6, 2.5 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 4.33-4.23 (m, 2H), 3.97(dd, J=9.7, 4.1 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 1H), 2.83 (dd, J=13.7,4.1 Hz, 1H), 2.69 (br s, 1H), 2.28 (dd, J=13.7, 9.7 Hz, 1H), 1.40 (s,3H), 1.33 (t, J=7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 172.9 (C),164.9 (C), 146.5 (CH), 137.7 (CH), 125.1 (C), 121.9 (C), 111.3 (CH),69.7 (CH), 61.8 (CH₂), 57.3 (CH), 53.7 (CH₃), 43.8 (C), 42.1 (CH₂), 21.9(CH₃), 14.3 (CH₃); IR (thin film): 3346, 2981, 2948, 2904, 2878, 2850,2235, 1736, 1609, 1495, 1285, 1205, 1028 cm⁻¹; HRMS (ESI) calculated forC₁₅H₁₉N₃O₃ (M−Na) 312.1324, observed 312.1329.

Rel-(3R,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile(16). In a 100 mL round bottom flask, pyrrolidine ester 15 (1.28 g, 4.42mmol) was dissolved in anhydrous CH₂Cl₂ (15 mL). The solution was cooledin an ice bath. To the solution was added Et₃N (740 μL, 5.3 mmol) and2-chloropropionyl chloride (470 μL, 4.9 mmol). The reaction wasmaintained for 1 h, by which time starting material had been consumed(by TLC). The reaction was quenched with H₂O (10 mL) and the biphasicmixture was stirred vigorously for 10 min. The biphasic mixture wasextracted with CH₂Cl₂ (3×20 mL). The organic layer was concentrated invacuo. The crude residue was dissolved in CH₂Cl₂ (20 mL) and a solutionof MeNH₂ (40% in H₂O) and the biphasic mixture was stirred vigorouslyfor 12 h. The mixture was extracted with CH₂Cl₂ (3×20 mL). Combinedextracts were dried over Na₂SO₄, filtered through cotton, andconcentrated in vacuo to afford a yellow foam. The residue was dissolvedin CH₂Cl₂ (10 mL) and MeOH (10 mL). The solution was stirred under astream of air until ca. 4 mL of solution remained. The suspension wascooled in the freezer for 18 h. Filtration afforded diketopiperazine 16(490 mg, 1.50 mmol, 34% yield as a colorless solid. ¹H NMR (600 MHz,CDCl₃): δ 7.97 (d, J=2.6 Hz, 1H), 7.37 (dd, J=8.6, 2.6 Hz, 1H), 6.76 (d,J=8.6 Hz, 1H), 4.87 (s, 1H), 4.37 (dd, J=11.3, 6.6 Hz, 1H), 3.92 (s,3H), 3.89 (q, J=7.3 Hz, 1H), 3.03 (s, 3H), 2.77 (dd, J=13.4, 11.4 Hz,1H), 2.50 (dd, J=13.4, 6.6 Hz, 1H), 1.69 (s, 3H), 1.48 (d, J=7.3 Hz,3H); ¹³C NMR (125 MHz, CDCl₃): δ 166.8 (C), 165.9 (C), 164.7 (C), 144.8(CH), 136.9 (CH), 125.4 (C), 119.9 (C), 111.5 (CH), 67.4 (CH), 60.9(CH), 56.2 (CH), 53.7 (CH₃), 42.5 (C), 36.9 (CH₂), 32.2 (CH₃), 25.1(CH₃), 15.5 (CH₃); IR (thin film): 2983, 2946, 2245, 1673, 1609, 1494,1402, 1288, 1026 cm⁻¹; HRMS (ESI) calculated for C₁₇H₂₀N₄O₃Na (M−Na)351.1433, observed 351.1430.

Rel-(3S,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile(18-1) andRel-(3S,6S,7S,8aS)-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epitrithiopyrrolo[1,2-a]pyrazine-7-carbonitrile(18-2). A 25 mL round bottom flask was charged with diketopiperazine 17(120 mg, 0.37 mmol) and S₈ (100 mg, 0.39 mmol) and anhydrous TH (3.7 mL)under Ar. The suspension was cooled in an ice bath. A solution of NaHMDS(0.6 M in PhMe, 3.7 mL, 2.2 mmol) was added over 2 min. The reaction wasmaintained for 2 h and quenched with saturated aqueous NH₄Cl (5 mL). Themixture was extracted with EtOAc (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.Flash chromatography (30×250 mm of SiO₂, 5% to 10% acetone in CH₂Cl₂)afforded a mixture of 18-1 and 18-2 (68 mg, 0.17 mmol, ca. 47% yield) asa yellow solid. Data for 17: ¹H NMR (600 MHz, CDCl₃): δ 8.16 (d, J=2.4Hz, 1H), 7.64 (dd, J=8.6, 2.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 4.86 (s,1H), 3.96 (s, 3H), 3.31 (d, J=15.0 Hz, 1H), 3.08 (s, 3H), 3.00 (d,J=15.0 Hz, 1H), 1.94 (s, 3H), 1.69 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ165.5 (C), 165.0 (C), 162.1 (C), 145.5 (CH), 137.3 (CH), 122.5 (C),120.2 (C), 111.7 (CH), 73.44 (C), 73.43 (C), 69.9 (CH), 53.8 (CH₃), 44.4(C), 42.9 (CH₂), 27.9 (CH₃), 24.4 (CH₃), 18.2 (CH₃); IR (thin film):2985, 2947, 2903, 2251, 1694, 1610, 1496, 1359, 1288, 1026 cm⁻¹; HRMS(ESI) calculated for C₁₇H₁₈N₄O₃S₂Na (M−Na) 413.0718, observed 413.0716.

Rel-S,S′-((3S,6S,7S,8aS)-7-cyano-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)diethanethioate (19, LEO-16-1839). Prepared in analogous fashion tocompound 5 from a mixture of 18-1 and 18-2 (52 mg, ca. 0.13 mmol) andacetic anhydride (40 μL, 0.42 mmol). Afforded 18 (37 mg, 0.078 mmol, 58%yield) as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ 8.25 (d, J=2.5Hz, 1H), 7.76 (dd, J=8.6, 2.5 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.90 (s,1H), 4.39 (d, J=14.6 Hz, 1H), 3.96 (s, 3H), 3.17 (s, 3H), 2.42 (d,J=14.6 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H), 1.69 (s, 3H);¹³C NMR (150 MHz, CDCl₃): δ 191.9 (C), 191.7 (C), 164.8 (C), 164.7 (C),162.8 (C), 145.5 (CH), 137.0 (CH), 124.0 (C), 120.8 (C), 111.5 (CH),73.6 (C), 72.0 (C), 71.1 (CH), 53.8 (CH₃), 44.7 (CH₂), 42.3 (C), 31.50(CH₃), 31.48 (CH₃), 31.0 (CH₃), 25.1 (CH₃), 23.7 (CH₃); IR (thin film):2980, 2923, 2850, 2361, 1686, 1610, 1496, 1365, 1288, 1109 cm⁻¹; HRMS(ESI) calculated for C₂₁H₂₄N₄O₅S₂Na (M−Na) 499.1086, observed 499.1077.

Rel-S,S′-((3S,6S,7S,8aS)-7-cyano-6-(6-methoxypyridin-3-yl)-2,3,7-trimethyl-1,4-dioxohexahydropyrrolo[1,2-a]pyrazine-3,8a(6H)-diyl)O,O′-dimethyl bis(carbonothioate) (20, LEO-16-1857). Prepared inanalogous fashion to compound 7 from a mixture of 17 and 18 (55 mg, 0.14mmol) and methyl chloroformate (30 μL, 0.39 mmol). Afforded 20 (44 mg,0.087 mmol, 61% yield) as a colorless solid. ¹H NMR (600 MHz, CDCl₃): δ8.22 (d, J=2.5 Hz, 1H), 7.77 (dd, J=8.7, 2.5 Hz, 1H), 6.80 (d, J=8.7 Hz,1H), 4.94 (s, 1H), 4.45 (d, J=14.8 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H),3.78 (s, 3H), 3.16 (s, 3H), 2.45 (d, J=14.8 Hz, 1H), 2.09 (s, 3H), 1.70(s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 166.5 (C), 166.4 (C), 165.1 (C),164.7 (C), 163.0 (C), 145.6 (CH), 136.9 (CH), 123.9 (C), 120.7 (C),111.5 (CH), 72.9 (C), 71.2 (CH), 70.9 (C), 55.0 (CH₃), 54.8 (CH₃), 53.7(CH₃), 45.1 (CH₂), 42.0 (C), 30.6 (CH₃), 25.0 (CH₃), 24.1 (CH₃); IR(thin film): 2984, 2954, 2255, 1731, 1688, 1496, 1366, 1289, 1190, 1129cm⁻¹; HRMS (ESI) calculated for C₂₁H₂₄N₄O₇S₂Na (M−Na) 531.0984, observed531.1003.

Rel-(4S,7S,8S,9aS)-7-(6-methoxypyridin-3-yl)-4,8,11-trimethyl-5,10-dioxo-2-thioxotetrahydro-7H-4,9a-(epiminomethano)pyrrolo[2,1-d][1,3,5]dithiazepine-8-carbonitrile(21, LEO-16-1858). Prepared in analogous fashion to compound 9 from amixture of 17 and 18 (54 mg, ca. 0.14 mmol) and phenylchlorothionoformate (30 μL, 0.22 mmol). Afforded 21 (22 mg, 0.56 mmol,36% yield) as a yellow solid. ¹H NMR (600 MHz, CDCl₃): δ 8.15 (d, J=2.5Hz, 1H), 7.49 (dd, J=8.7, 2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 5.01 (s,1H), 3.99 (s, 3H), 3.18-3.14 (m, 5H), 1.94 (s, 3H), 1.76 (s, 3H); ¹³CNMR (150 MHz, CDCl₃): δ 213.7 (C), 165.0 (C), 164.5 (C), 161.5 (C),145.6 (CH), 136.7 (CH), 122.6 (C), 119.7 (C), 112.0 (CH), 75.0 (C), 73.0(C), 71.3 (CH), 53.9 (CH₃), 45.8 (CH₂), 43.0 (C), 28.7 (CH₃), 24.7(CH₃), 19.9 (CH₃); IR (thin film): 2985, 2946, 2240, 1690, 1495, 1369,1288, 1002, 731 cm⁻¹; HRMS (ESI) calculated for C₁₈H₁₈N₄O₃S₃Na (M−Na)457.0439, observed 457.0425.

Leo-16-1862 v(R, S, S, S)-enentiomer. 1H NMR (600 MHz, CDCl₃): δ 7.11(d, J=1.9 Hz, 1H), 7.00 (dd, J=8.1, 1.9 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H),6.06 (s, br, 1H), 5.07 (s, 1H), 4.33 (d, J=14.3 Hz, 1H), 3.77-3.73 (m,4H), 3.25 (s, 3H), 2.96 (d, J=14.1 Hz, 1H), 2.83 (d, J=14.1 Hz, 1H),2.76-2.72 (m, 4H), 2.56 (d, J=14.3 Hz, 1H), 2.48 (s, 3H), 2.43 (s, 3H),2.16 (s, 3H). HRMS (ESI) calculated for C26H30N4O7S2Na (M−Na) 597.1454,observed 597.1446.

Leo-16-1866 (racemate). 1H NMR (600 MHz, CDCl₃): δ 8.36 (d, J=2.5 Hz,1H), 7.92 (dd, J=8.7, 12.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.15 (s,1H), 4.36 (d, J=14.5 Hz, 1H), 4.01 (s, 3H), 3.76-3.73 (m, 4H), 3.23 (s,3H), 2.90 (d, J=14.0 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 2.73-2.71 (m,4H), 2.56 (d, J=14.5 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).HRMS (ESI) calculated for C25H31N5O6S2Na (M−Na) 584.1614, observed584.1619.

Leo-16-1867 (racemate). 1H NMR (600 MHz, CDCl₃): δ 8.36 (d, J=2.5 Hz,1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.15 (s, 1H),4.35 (d, J=14.0 Hz, 1H), 4.01 (s, 3H), 3.513.46 (m, 4H), 3.23 (s, 3H),2.91 (d, J=13.8 Hz, 1H), 2.88 (d, J=13.8 Hz, 1H), 2.69-2.64 (m, 4H),2.56 (d, J=14.0 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H), 1.51(s, 9H). HRMS (ESI) calculated for C30H40N6O72Na (M−Na) 683.2297,observed 683.2299.

Leo-16-1868 (racemate). 1H NMR (600 MHz, CDCl₃): δ 8.66 (d, J=2.7 Hz,1H), 8.05 (dd, J=8.3, 2.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 5.25 (s, 1H),4.40 (d, J=14.6 Hz, 1H), 3.79-3.74 (m, 4H), 3.23 (s, 3H), 2.91 (d,J=14.7 Hz, 1H), 2.88 (d, J=14.7 Hz, 1H), 2.74-2.70 (m, 4H), 2.54 (d,J=14.6 Hz, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H). HRMS (ESI)calculated for C24H28ClN5O5S2Na (M−Na) 588.1118, observed 588.1125.

Leo-16-1869 (racemate). 1H NMR (600 MHz, CDCl₃): δ 8.28 (d, J=2.8 Hz,1H), 8.04 (dd, J=8.5, 2.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 5.25 (s, 1H),4.39 (d, J=14.7 Hz, 1H), 3.52-3.46 (m, 4H), 3.22 (s, 3H), 2.90 (t,J=13.9 Hz, 2H), 2.68-2.64 (m, 4H), 2.53 (d, J=14.7 Hz, 1H), 2.45 (s,3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.10 (s, 9H). HRMS (ESI) calculated forC29H37ClN606S2Na (M−Na) 687.1802, observed 687.1811.

Leo-17-1876 (S, R, R, R)-enentiomer). 1H NMR (600 MHz, CDCl₃): δ 7.10(d, J=1.9 Hz, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H),6.05 (d, J=1.6 Hz, 1H), 6.04 (d, J=1.6 Hz, 1H), 5.06 (s, 1H), 4.31 (d,J=14.8 Hz, 1H), 3.48-3.46 (m, 4H), 3.24 (s, 3H), 2.95 (d, J=13.7 Hz,1H), 2.84 (d, J=13.7 Hz, 111), 2.69-2.66 (m, 4H), 2.55 (d, J=14.8 Hz,1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.14 (s, 3H), 1.50 (s, 9H). HRMS (ESI)calculated for C31H39N5O8S2Na (M−Na) 696.2138, observed 696.2135.

Example 14

Cell Viability Assay of Compound (2) against CTCL

Compound (2) (FIG. 8A) was tested in a cell viability assay using HUT78cells in a CELLTITER-GLO® assay. To determine IC₅₀ value of Compound (2)against human CTCL HUT78 cells, viability assay was performed usingCELLTITER-GLO® Reagent as described by the supplier (Promega, Madison,Wis.). Briefly, cells (7500/well) were seeded in opaque 96-well platesand exposed to Compound (1) in a dose-dependent manner for 72 h at 37°C. in 5% CO₂. After 72 h treatment with compound (1), CELLTITER-GLO®Reagent (50 L/well) was added to 96-well plates. Viable cells which aremetabolically active are directly proportional to the ATP present.Luminescent signals correlate with the amount of ATP present in cells.After 10 min incubation with CELLTITER-GLO® Reagent, luminescence wasmeasured at an integration time of 1 second/well using an automated BMGplate reader. Dimethyl sulfoxide (DMSO) was used as the vehicle control.Each experiment was conducted in triplicate. IC₅₀ values were determinedusing CalcuSyn software (Biosoft).

An IC₅₀ value of 2.8 nM was determined for compound (2). See FIG. 8B.Analysis of the results demonstrates that the compound (2) exhibits inantitumor activities against CTCL.

1. A method for treating T-cell lymphoma in a subject in need thereof,comprising administering to the subject, a compound having the structureof formula (1):

wherein: R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C), —NO₂,—SR^(1D), —SO_(n1)R^(1B), —SO_(n1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A),—CONR^(2B)R^(2C), —NO₂, —SR^(2D), —SO_(n2)R^(2B), —SO_(n2)OR^(2B),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(3A),—NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(4A), —NR^(4B)R^(4C), —COOR^(4A),—CONR^(4B)R^(4C), —NO₂, —SR^(4D), —SO_(n4)R^(4B), —SO_(n4)OR^(4B),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(5A),—NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C), —NO₂, —SR^(5D),—SO_(n5)R^(5B), —SO_(n5)OR^(5B), SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂,—SR^(6D), —SO_(n6)R^(6B), —SO_(n6)OR^(6B), SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(16A), —NR^(16B)R^(16C), —COOR^(16A),—CONR^(16B)R^(16C), —NO₂, —SR^(16D), —SO_(n16)R¹⁶, —SO_(n16)OR^(16B),—SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C), ONR^(16B)R^(16C),—NHC(O)NHNR^(16B)R^(6C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(18A),—NR^(18B)R^(18C), —COOR^(18A), —CONR¹⁸BR^(18C), —NO₂, —SR^(18D),—SO_(n18)R^(18B), —SO_(n18)OR^(18B), —SO_(v18)NR^(18B)BR^(18C),—NHNR¹⁸BR^(18C), —ONR^(18B)R^(18C), —NHC(O)NHNR^(18B)R^(18C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R²⁸ is —SR²⁵ and R²⁹ is —SR²⁶,wherein R²⁸ and R²⁹ are optionally joined to form *—S_(p)—* wherein p isan integer from 2 to 4 and each * represents the point of attachment tothe remainder of the compound; R²⁵ is hydrogen, —C(O)-L¹-R³²,—C(S)-L¹-R³², substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R²⁶ is hydrogen, —C(O)-L²-R³³,—C(S)-L²-R³³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R²⁵ and R²⁶ may optionally bejoined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene; L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene; R³² and R³³ are independently halogen, substituted orunsubstituted C₁-C₃ alkyl, substituted or unsubstituted aryl; R^(1A),R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C),R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B), R^(6C),R^(16D), R^(18A), R^(18B), R^(18C), and R^(18D) are independentlyhydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; X is independently —F, —Cl, —Br, or —I; n1,n2, n3, n4, n5, n6, n16, and n18 are independently an integer from 1 to4; and v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2; ora pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein R¹¹ is substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; and/or R¹⁶ is hydrogen.
 3. (canceled)
 4. The method of claim1, wherein the compound having the structure of formula (I):


5. The method of claim 4, wherein: R³ and R⁴ are independently hydrogenor unsubstituted methyl; R¹ is —CN, —COOR^(1A), —CONR^(1B)R^(1C), orsubstituted or unsubstituted heteroalkyl; R² is —CF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl; R⁵ and R⁶ are independently hydrogen, halogen,substituted or unsubstituted alkyl, or substituted or unsubstitutedcycloalkyl; and/or p is
 2. 6-14. (canceled)
 15. The method of claim 4,wherein the compound of formula (I) has the structure of formula (II):

wherein, X is —CR^(21A)R^(21B), —O—, —NR^(21C), or —S—; X² is—CR^(22A)R^(22B)—, —O—, —NR^(22C)—, or —S—; R⁷ is hydrogen, halogen,—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(7A), —NR^(7B)R^(7C),—COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D), —SO_(n7)R^(7B),—SO_(n7)OR^(7B), SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C),—NO₂, —SR^(10D), —SO_(n10)R^(10B), —SO_(n10)OR^(10B),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(11A), —NR^(11B)R^(11C), —COOR^(11A), —CONR^(11B)R^(11C), —NO₂,—SR^(11D), —SO_(n11)R^(11B), —SO_(n11)OR^(11B), SO_(v11)NR^(11B)R^(11C),—NHNR^(11B)R^(11C), —ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ are optionallyjoined together to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl; R¹² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(12A),—NR^(12B)R^(12C), —COOR^(12A), —CONR^(12B)R^(12C), —NO₂, —SR^(12D),—SO_(n12)R^(12B), —SO_(n12)OR^(12B), SO_(v12)NR^(12B)R^(12C),—NHNR^(12B)R^(12C), —ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(13A), —NR^(13B)BR^(13C),—COOR^(13A), —CONR^(13B)R^(13C), —NO₂, —SR^(13D), —SO_(n13)R^(13B),—SO_(n13)OR^(13B), SO_(v13)NR^(13B)R^(13C), —NHNR^(13B)R^(13C),—ONR^(13B)R^(13C), —NHC(O)NHNR^(13B)R^(13C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(21A), R^(21B), R^(22A), and R^(22B), areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(7A), R^(7B), R^(7C), R^(7C),R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B), R^(11C), R^(11D),R^(12A), R^(12B), R^(12C), R^(12D), R^(13A), R^(13B), R^(13C), R^(13D),R^(21C) and R^(22C) are independently hydrogen, —CX₃, —CN, —COOH,—CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; n7, n10,n11, n12 and n13 are independently 1 or 4; v7, v10, v11, v12 and v13 areindependently 1 or 2; and p is 2 or 3; or a pharmaceutically acceptablesalt thereof.
 16. (canceled)
 17. The method of claim 17, wherein X¹ andX² are independently —O— or —S—; and p is
 2. 18. (canceled)
 19. Themethod of claim 15, wherein the compound of formula (II(S)) has thestructure of formula (III(S)):


20. The method of claim 19, wherein: R¹ is —CN, —OR^(1A), —COOR^(1A), or—CONR^(1B)R^(1C), and wherein R^(1A), R^(1B), and R^(1C) areindependently hydrogen, or substituted or unsubstituted alkyl; whereinR² is —CF₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl, wherein R³ and R⁴ arehydrogen, wherein R¹² and R¹³ are independently hydrogen orunsubstituted methyl; and/or wherein R¹⁰ and R¹¹ are hydrogen. 21-27.(canceled)
 28. The method of claim 4, wherein the compound is:


29. (canceled)
 30. The method of claim 1, wherein the compound has theformula (XXI):


31. The method of claim 30, wherein the compound has the formula (XXII):

wherein: X³ is —N═ or —CR⁷═; X⁴ is —N═ or —CR⁸═; X⁵ is —N═ or —CR⁹═; R⁷is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(7A), —NR^(7B)R^(7C), —COOR^(7A), —CONR^(7B)R^(7C), —NO₂, —SR^(7D),—SO_(n7)R^(7B), SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C),—NHC(O)NHNR^(7B)R^(7C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁸ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(8A),—NR^(8B)R^(8C), —COOR^(8A), —CONR^(8B)R^(8C), —NO₂, —SR^(8D),—SO_(n8)R^(8B), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁷ and R⁸ may optionally be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(9A), —NR^(9B)R^(9C), —COOR^(9A), —CONR^(9B)R^(9C), —NO₂, —SR^(9D),—SO_(n9)R^(9B), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁸ and R⁹ may optionally be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;R¹⁰ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(10A), —NR^(10B)R^(10C), —COOR^(10A), —CONR^(10B)R^(10C), —NO₂,—SR^(10D), —SO_(n10)R^(10B)R^(10C), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)BR^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(11A), —NR^(11B)R^(11C),—COOR^(11A), —CONR^(11B)R^(11C), —NO₂, —SR^(11D), —SO_(n11)R^(11B),—SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C), —ONR^(11B)R^(11C),—NHC(O)NHNR^(11B)R^(11C) substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(7A),R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(11A), R^(11B),R^(11C) and R^(11D) are independently hydrogen, halogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(7B) and R^(7C), R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) andR^(10C), and R^(11B) and R^(11C), substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; n7, n8, n9, n10 and n11 are independently an integer from 1to 4; and v7, v8, v9, v10 and v11 are independently 1 or
 2. 32. Themethod of claim 31, wherein R⁷ and R⁸ or R⁸ and R⁹ are joined to form asubstituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl having structural formula:

wherein: X¹ is —CR^(21A)R^(21B)—, —O—, —NR^(21C)—, or —S—; X² is—CR^(22A)R^(22B)—, —O—, —NR^(22C)—, or —S—; R¹² is hydrogen, halogen,—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(12A), —NR^(12B)R^(12C),—COOR^(12A), —CONR^(12B)R^(12C), —NO₂, —SR^(12D), —SO_(n12)R^(12B),—SO_(n12)OR^(12B), SO_(v12)NR^(12B)R^(12C), —NHNR^(12B)R^(12C),—ONR^(12B)R^(12C), —NHC(O)NHNR^(12B)R^(12C) substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(13A), —NR^(13B)R^(13C), —COOR^(13A), —CONR^(13B)R^(13C),—NO₂, —SR^(13D), —SO_(n13)R^(13B), —SO_(v12)OR^(13B),SO_(v12)NR^(13B)R^(13C), —NHNR^(13B)R^(13C), —ONR¹³BR^(13C),—NHC(O)NHNR^(13B)R^(13C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁷is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(27A),—NR^(27B)R^(27C), —COOR^(27A), —CONR^(27B)R^(27C), —NO₂, —SR^(27D),—SO_(n27)R^(27B), —SO_(n27)OR^(27B), —SO_(v27)NR^(27B)R^(27C),—NHNR^(27B)R^(27C), —ONR^(27B)R^(27C), —NHC(O)NHNR^(27B)R^(27C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(21A), R^(21B), R^(22A), andR^(22B) are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(21C),R^(22C), R^(27A), R^(27B), R^(27C), and R^(27D) are independentlyhydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; n12, n13, and n27 are independently an integerfrom 1 to 4; v12, v13 and v27 are independent 1 or 2; m is 1 or 2; z5 isan integer from 0 to 8; or a pharmaceutically acceptable salt thereof.33. (canceled)
 34. The method of claim 31, wherein the compound has theformula:


35. (canceled)
 36. The method of claim 31, wherein the compound has theformula:


37. (canceled)
 38. The method of claim 31, wherein the compound has theformula:


39. (canceled)
 40. The method of claim 30, wherein the compound has theformula:

wherein: X⁶ is —N═ or —CR^(23A)═; X⁷ is —CR^(24A)R^(24B)—, —S—, —O—, or—NR^(24C)—; R¹⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(19A), —NR^(19B)R^(19C), —COOR^(19A), —CONR¹⁹BR^(19C),—NO₂, —SR^(19D), SO_(n19)R^(19B), —SO_(v19)NR^(19B)R^(19C),—NHNR^(19B)R^(19C), —ONR^(19B)R^(19C), —NHC(O)NHNR^(19B)R^(19C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R²⁰ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(20A), —NR^(20B)R^(20C),—COOR^(20A), —CONR^(20B)R^(20C), —NO₂, —SR^(20D), —SO_(n20)R^(20B),SO_(v20)NR^(20B)R^(20C), —NHNR^(20B)R^(20C), —ONR^(20B)R^(20C),—NHC(O)NHNR^(20B)R^(20C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(23A), R^(24A), and R^(24B) are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(19A), R^(19B), R^(19C), R^(19D), R^(20A), R^(20B),R^(20C), R^(20D), and R^(24C) are independently hydrogen, halogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; n19and n20 are independently an integer from 1 to 4; and v19 and v20 areindependent 1 or
 2. 41. (canceled)
 42. The method of claim 31, whereinR¹⁰ and R¹¹ are independently hydrogen; X⁴ is —N═; R⁷ is —OCH₃; R² issubstituted or unsubstituted alkyl; and/or R¹ is —CN. 43-48. (canceled)49. The method of claim 30, wherein: R²⁵ is —C(O)-L¹-R³² or—C(S)-L¹-R³²; and R²⁶ is —C(O)-L²-R³³ or —C(S)-L²-R³³.
 50. (canceled)51. The method of claim 49, wherein: i) L¹ and L² are independently abond, —O—, or —NH—; or ii) L¹ is -L^(1A)-L^(1B)-, wherein L^(1A) isbonded to —C(O)— or —C(S)—; L² is -L^(2A)-L^(2B)-, wherein L^(2A) isbonded to —C(O)— or —C(S)—; L^(1A) is a bond or —(CH₂)_(z1)—; L^(1B) isa bond, —O— or —NR^(30B)—; L^(2A) is a bond or —(CH₂)_(z2)—; L^(2B) is abond, —O— or —NR^(31B)—; z1 and z2 are independently an integer from 1to 10; and R^(30B) and R^(31B) are independently hydrogen or substitutedor unsubstituted alkyl. 52-53. (canceled)
 54. The method of claim 49,wherein R³² and R³³ are independently unsubstituted C₁-C₃ alkyl orunsubstituted aryl; R³² and R³³ are independently halogen; or R²⁵ andR²⁶ are joined together to form:

55-56. (canceled)
 57. The method of claim 30, wherein R⁶ is methyl. 58.The method of claim 30, wherein the compound has the structure:


59. The method of claim 1, wherein the T-cell lymphoma is cutaneousT-cell lymphoma (CTCL), peripheral T-cell lymphoma, anaplasticlarge-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cellLeukemia/Lymphoma, blastic natural killer (NK) cell lymphoma,enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma,lymphoblastic lymphoma, or nasal natural killer (NK)/T-cell lymphoma,wherein the cutaneous T-cell lymphoma is Sezary syndrome, mycosisfungoides, folliculotropic mycosis fungoides, pagetoid reticulosis,granulomatous slack skin, primary cutaneous CD30+ T-celllymphoproliferative disorders, lymphomatoid papulosis, primary cutaneousanaplastic large-cell lymphoma, primary cutaneous γδ T-cell lymphoma,primary cutaneous CD8+ aggressive epidermotropic lymphoma, primarycutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, orprimary cutaneous CD4+ T-ceil lymphoma.
 60. (canceled)
 61. The method ofclaim 1, wherein the T-cell lymphoma is associated with at least one ofthe following conditions: smoking, obesity, infection, HIV, Epstein-Barrvirus, human T-lymphotropic virus, Helicobacter pyroli infection,chronic Helicobacter pyroli infection, exposure to chemicals, exposureto insecticides, exposure to pesticides, use of immunosuppressant drugs,weakened immune system, genetic disorders, previous chemotherapy, andprevious radiation therapy.
 62. The method of claim 1, furthercomprising administering to the subject an additional therapeutic agentused in the treatment of T-cell lymphoma, wherein the additionaltherapeutic agent is alemtuzumab, bendamustine, bexarotene, bleomycin,bortezomib, brentuximab vedotin, carboplatin, carfilzomib, carmustine,cisplatin, cyclophosphamide, cytarabine, dacarbazine, dazatinib,denileukin diftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate prednisone,prednisolone, psoralen, retinoids resiquimod rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof.
 63. (canceled)
 64. Apharmaceutical composition for treating T-cell lymphoma comprising anETP derivative, at least one additional therapeutic agent used in thetreatment of T-cell lymphoma, and at least one pharmaceuticallyacceptable excipient.
 65. The pharmaceutical composition of claim 64,wherein the ETP derivative is a compound having the structure of formula(1):

wherein, R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(1A), —NR^(1B)R^(1C), —COOR^(1A), —CONR^(1B)R^(1C)—NO₂,—SR^(1D), —SO_(n1)R^(1B), —SO_(n1)OR^(1B), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(2A), —NR^(2B)R^(2C), —COOR^(2A),—CONR^(2B)R^(2C), —NO₂, —SR^(2D), —SO_(n2)R^(2B), —SO_(n2)OR^(2B),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(3A),—NR^(3B)R^(3C), —COOR^(3A), —CONR^(3B)R^(3C), —NO₂, —SR^(3D),—SO_(n3)R^(3B), —SO_(n3)OR^(3B), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(4A), —NR^(4B)R^(4C), —COOR^(4A),—CONR^(4B)R^(4C), —NO₂, —SR^(4D), —SO_(n4)R^(4B), —SO_(n4)OR^(4B),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(5A),—NR^(5B)R^(5C), —COOR^(5A), —CONR^(5B)R^(5C), —NO₂, —SR^(5D),—SO_(n5)R^(5B), —SO_(n5)OR^(5B), SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(6A), —NR^(6B)R^(6C), —COOR^(6A), —CONR^(6B)R^(6C), —NO₂,—SR^(6D), —SO_(n6)R^(6B), —SO_(n6)OR^(6B), SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(16A), —NR^(16B)R^(16C), —COOR^(16A),—CONR^(16B)R^(16C), —NO₂, —SR^(16D), —SO_(n16)R^(16B),—SO_(n16)OR^(16B), —SO_(v16)NR^(16B)R^(16C), —NHNR^(16B)R^(16C),ONR^(16B)R^(16C), —NHC(O)NHNR^(16B)R^(16C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(18A), —NR^(18B)R^(18C), —COOR^(18A), —CONR^(18B)R^(18C),—NO₂, —SR^(18D), —SO_(n18)R^(18B), —SO_(n18)OR^(18B),—SO_(v18)NR^(18B)R^(18C), —NHNR^(18B)R^(18C), —ONR^(18B)R^(18C),—NHC(O)NHNR^(18B)R^(18C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁸is —SR²⁵ and R²⁹ is —SR²⁶, wherein R²⁸ and R²⁹ are optionally joined toform *—S_(p)—* wherein p is an integer from 2 to 4 and each * representsthe point of attachment to the remainder of the compound; R²⁵ ishydrogen, —C(O)-L¹-R³², —C(S)-L¹-R³², substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁶ ishydrogen, —C(O)-L²-R³³, —C(S)-L²-R³³, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁵ andR²⁶ may optionally be joined to form

L¹ is a bond, —O—, —NH—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene; L² is a bond, —O—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene; R³² and R³³ are independently halogen, substituted orunsubstituted C₁-C₃ alkyl, substituted or unsubstituted aryl; R^(1A),R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C),R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(16A), R^(16B), R^(16C),R^(16D), R^(18A), R^(18B), R^(18C) and R^(18D) are independentlyhydrogen, halogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; X is independently —F, —Cl, —Br, or —I; n1,n2, n3, n4, n5, n6, n16, and n18 are independently an integer from 1 to4; and v1, v2, v3, v4, v5, v6, v16, and v18 are independently 1 or 2; ora pharmaceutically acceptable salt thereof.
 66. The pharmaceuticalcomposition of claim 64, wherein the additional therapeutic agent isalemtuzumab, bendamustine, bexarotene, bleomycin, bortezomib,brentuximab vedotin, carboplatin, carfilzomib, carmustine, cisplatin,cyclophosphamide, cytarabine, dacarbazine, dazatinib, denileukindiftitox, dexamethasone, doxorubicin, etoposide, everolimus,fludarabine, forodesine, gemcitabine, hydroxydaunorubicin, ifosfamide,imiquimod, interferons, lenalidomide, liposomal doxorubicin,mechlorethamine, methotrexate, methylprednisolone, nelfinavir, oralcorticosteroids, panobinostat, pentostatin, pralatrexate, prednisone,prednisolone, psoralen, retinoids, resiquimod, rituximab, romidepsin,SGX301, temsirolimus, topical corticosteroids, vinblastine, vincristine,vinorelbine, vorinostat, or a combination thereof.